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Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence ( NBAS ) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene. [ABSTRACT FROM AUTHOR]

Melorheostosis (MEL) is the rare sporadic dysostosis characterized by monostotic or polyostotic osteosclerosis and hyperostosis often distributed in a sclerotomal pattern. The prevailing hypothesis for MEL invokes postzygotic mosaicism. Sometimes scleroderma-like skin changes, considered a representation of the pathogenetic process of MEL, overlie the bony changes, and sometimes MEL becomes malignant. Osteopoikilosis (OPK) is the autosomal dominant skeletal dysplasia that features symmetrically distributed punctate osteosclerosis due to heterozygous loss-of-function mutation within LEMD3 . Rarely, radiographic findings of MEL occur in OPK. However, germline mutation of LEMD3 does not explain sporadic MEL. To explore if mosaicism underlies MEL, we studied a boy with polyostotic MEL and characteristic overlying scleroderma-like skin, a few bony lesions consistent with OPK, and a large epidermal nevus known to usually harbor a HRAS, FGFR3, or PIK3CA gene mutation. Exome sequencing was performed to ~ 100 × average read depth for his two dermatoses, two areas of normal skin, and peripheral blood leukocytes. As expected for non-malignant tissues, the patient's mutation burden in his normal skin and leukocytes was low. He, his mother, and his maternal grandfather carried a heterozygous, germline, in-frame, 24-base-pair deletion in LEMD3 . Radiographs of the patient and his mother revealed bony foci consistent with OPK, but she showed no MEL. For the patient, somatic variant analysis, using four algorithms to compare all 20 possible pairwise combinations of his five DNA samples, identified only one high-confidence mutation, heterozygous KRAS Q61H (NM_033360.3:c.183A > C, NP_203524.1:p.Gln61His), in both his dermatoses but absent in his normal skin and blood. Thus, sparing our patient biopsy of his MEL bone, we identified a heterozygous somatic KRAS mutation in his scleroderma-like dermatosis considered a surrogate for MEL. This implicates postzygotic mosaicism of mutated KRAS , perhaps facilitated by germline LEMD3 haploinsufficiency, causing his MEL. [ABSTRACT FROM AUTHOR]

Brachydactyly includes shortening of digits due to abnormal development of phalanges, metacarpals, or both. It can occur either as an isolated malformation or with other anomalies as part of many congenital syndromes. It is included as one of the dysostosis groups affecting the limbs in the nosology and classification of genetic skeletal disorders. However, brachydactyly usually shows a high degree of phenotypic variability. In this study, we successfully identified a novel heterozygous mutation of the parathyroid hormone-like hormone ( PTHLH ) gene by exome sequencing in a Chinese pedigree with brachydactyly and short stature. The PTHLH gene encodes a parathyroid hormone-related protein (PTHrP) that is involved in the regulation of endochondral bone development, and mutations in this gene cause the type E form of brachydactyly. The mutation p.L15R occurs at a hydrophobic core region of the signal peptide, suggesting that this variation probably changes the signal peptide cleavage site at the in silico prediction. Further in vitro functional analysis showed that this mutation can lead to the retention of an N-terminal signal peptide fragment after the nascent proteins are translated. [ABSTRACT FROM AUTHOR]

The article describes the case of surgical correction of severe kyphoscoliosis resulting in a neurological complication in Marshall-Smith syndrome (MSS). MSS is a rare syndrome described by facial dysostosis, respiratory difficulties, mental retardation, and short height. MSS is thought to be linked to NFIX gene mutation.

Abstract: Skeletal patterning is tightly linked to embryonic morphogenesis. Accumulated evidence on genotype–phenotype analyses in model animals and human has uncovered molecular signals that participate in skeletal size, shape, and spatial organization. Embryonic morphogenesis endows morphological information to groups of skeletal precursors. Accordingly, some of the congenital skeletal disorders are manifested as defects in embryogenesis prior to skeletal tissue differentiation and pathologically categorized as dysostosis. Spondylocostal dysostosis (SCDO) and spondylothoracic dysostosis (STDO) are skeletal disorders that are highly specific to the axial skeleton, vertebrae, and ribs, whose embryonic origin is the segmented mesodermal structure called somite. The genes responsible for these diseases have recently been identified and are operated during somite formation. Current investigations on organogenesis of mouse models of SCDO and STDO uncovered the existence of more complicated regulatory steps for the spatiotemporal organization of the axial skeleton than the original view of direct link between morphogenesis and skeletal patterning. Molecular and cellular findings in axial skeleton development are expected to contribute to develop more efficient therapeutic strategies against common medical problems. [Copyright &y& Elsevier]

Nager syndrome (preaxial acrofacial dysostosis) is rare and mostly sporadic. We present a case of Nager syndrome in Taiwan. Craniofacial findings included micrognathia, malar hypoplasia, downslanting palpebral fissures, cleft palate, and ear anomalies. Radial defects consisted of hypoplastic thumb, short forearm, and proximal radioulnar synostosis. Patent ductus arteriosus, atrial septal defect, lower limb deformities, and uncommon flat nasal bridge were noted. Nasal endotube passing through a narrowing oropharynx region or oral airway is life-saving before tracheostomy is performed on patients with Nager syndrome and restricted jaw opening and glossoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Mucopolysaccharidoses (MPS) are a group of inherited metabolic disorders caused by a deficiency of specific lysosomal enzymes. The ubiquitous nature of GAG within the connective tissue of the body results in a wide range of clinical effects. The suspicion of MPS disorder must be raised on musculoskeletal complications: evolving joint pain and joint contractures in the absence of inflammation; growth failure; radiographic abnormalities designated dysostosis multiplex associated with low bone mineral density. Glycogen storage diseases (GSD) are inherited disorders that affect glycogen metabolism. The glycogen found in these disorders is abnormal in quantity, quality or both. GSD that mainly affect the liver usually have hepatomegaly and hypoglycemia as the presenting features. The predominant clinical features of GSD that mainly affect the muscle are muscle cramps, exercise intolerance, susceptibility to fatigue, and progressive weakness. Other musculoskeletal manifestations are growth failure (GSD I, III, VI, VII, IX), hyperuricemia and gout (GSD I, III, V and VII) and osteoporosis (GSD I, II, III). [Copyright &y& Elsevier]

Summary: Cleidocranial dysplasia or dysostosis involves dental anomalies, bone abnormalities with membranous ossification (clavicles, cranium, face, pelvis), rarely of the spine and the remainder of the skeleton. We report 2 new cases and describe the different clinical aspects of this disorder and the orthopedic problems that it can pose. The clinical demonstrations of this disease are highly variable and inconsistent, which explains the diversity of circumstances of discovery. Abnormalities of the face and clavicles, as well as of pelvic ossification are most frequent and can be regarded as major signs. These clinical demonstrations do not require treatment in the majority of the cases. Dental anomalies, coxa vara and scoliosis require regular monitoring and treatment in the event of progressive aggravation. The incomplete penetrance of this autosomal dominant disease and its good tolerance explain the frequency of undiagnosed forms, whose clinical expression is discrete. [Copyright &y& Elsevier]

Abstract: Objective: The purpose of this study was to provide a description of the language and speech (intelligibility, voice, resonance, articulation) in a 7-year-old Dutch speaking boy with Nager syndrome. To reveal these features comparison was made with an age and gender related child with a similar palatal or hearing problem. Methods: Language was tested with an age appropriate language test namely the Dutch version of the Clinical Evaluation of Language Fundamentals. Regarding articulation a phonetic inventory, phonetic analysis and phonological process analysis was performed. A nominal scale with four categories was used to judge the overall speech intelligibility. A voice and resonance assessment included a videolaryngostroboscopy, a perceptual evaluation, acoustic analysis and nasometry. Results: The most striking communication problems in this child were expressive and receptive language delay, moderately impaired speech intelligibility, the presence of phonetic and phonological disorders, resonance disorders and a high-pitched voice. The explanation for this pattern of communication is not completely straightforward. The language and the phonological impairment, only present in the child with the Nager syndrome, are not part of a more general developmental delay. The resonance disorders can be related to the cleft palate, but were not present in the child with the isolated cleft palate. One might assume that the cul-de-sac resonance and the much decreased mandibular movement and the restricted tongue lifting are caused by the restricted jaw mobility and micrognathia. To what extent the suggested mandibular distraction osteogenesis in early childhood allows increased mandibular movement and better speech outcome with increased oral resonance is subject for further research. Conclusion: According to the results of this study the speech and language management must be focused on receptive and expressive language skills and linguistic conceptualization, correct phonetic placement and the modification of hypernasality and nasal emission. [Copyright &y& Elsevier]

Abstract: The Yunis–Varón syndrome (YVS) represents a rare autosomal recessive syndrome of easy recognition characterized by cleidocraneal dysplasia, absence of thumbs and halluces, distal aphalangia, ectodermal anomalies, and poor outcome. Here, we report two sisters with YVS who also had papillo-macular atrophic chorioretinopathy with “salt-and-pepper” appearance that could not be attributed to environmental or metabolic causes. Our best hypothesis is that the ocular findings in our two patients are part of the phenotypic manifestations of YVS. We suggest that an extensive ophthalmologic examination should be carried out in all children with YVS in order to define the frequency and nature of the ocular findings in these patients. [Copyright &y& Elsevier]

Summary: Nager acrofacial dysostosis is a rare congenital syndrome characterized by malformed mandibulofacial structures and pre-axial upper limbs. Trismus and glossoptosis from mandibular abnormalities predisposes infants to life-threatening respiratory distress. A case of a Nager Syndrome mother delivering a similarly afflicted fetus is presented, with approaches to maintaining both tenuous airways described. Distinguishing this condition from similar syndromes is critical for care and prognosis. [Copyright &y& Elsevier]

Abstract: We report two new female patients with typical features of Catel–Manzke syndrome (MIM 302380) and the follow-up of the first patient affected by this syndrome. In addition to the Pierre Robin anomaly, the hallmark of this palatodigital syndrome is a bilateral hyperphalangy and clinodactyly of the index finger. Classified into four groups there are now (1) 23 reported cases of the typical, (2) six cases of the extended Catel–Manzke syndrome showing more than two accessory bones in the hand, (3) two patients showing unilateral hyperphalangy and clinodactyly of the index finger (4) two patients described with isolated features of the “Manzke dysostosis” without Pierre Robin anomaly. The karyotype of our three patients was normal. A search for submicroscopic chromosomal abnormalities by array CGH was performed. In addition, we sequenced candidate genes which are known to be involved in phalangeal development. However, no pathogenic aberrations or mutations were found. [Copyright &y& Elsevier]

Abstract: Casamassima–Morton–Nance syndrome belongs to the heterogeneous group of spondylocostal dysostoses (SCD) represented by a large heterogeneous group in which diverse diagnoses, associations and modes of inheritance are found. Common features include segmentation abnormalities of the vertebrae and ribs. Here, we report on a fetal case with spondylocostal dysostosis, anal and genitourinary malformations and discuss Casamassima–Morton–Nance syndrome. [Copyright &y& Elsevier]

Background: The observation that some patients with schizophrenia display subtly anomalous craniofacial features dates back to the early 1900s and has recently been hypothesized to reflect disrupted prenatal development also involving the brain. Most studies to date have used observer ratings rather than physical measurements and have studied only Caucasian samples. Our objective was to determine whether schizophrenia is associated with craniofacial anomalies applying quantitative methods in Caucasian and African American subjects. Methods: Participants were 32 Caucasian and 20 African American outpatients aged 18 to 60, meeting Structured Clinical Interview for DSM-IV (SCID) confirmed criteria for schizophrenia/schizoaffective disorder, recently discharged from a psychiatric hospital in Queens, New York. The healthy control subjects were recruited through local advertisements and were individually matched to the patient sample on gender, race, and age. Results: Thirty-two measurements of the head and face reflecting all regions of potential developmental significance were taken according to published methods and validated for this study. Significantly greater skull base width [F(1,51) = 13.11, p = .0005] and greater height of the cutaneous lower lip [F(1,51) = 7.90, p = .0059] were found among patients after applying multiplicity correction. Statistical correction for group differences in body weight did not alter the findings. Conclusions: Findings agree with the two major anthropometric studies in schizophrenia. [Copyright &y& Elsevier]

Summary: Objective:: To describe the otologic and audiologic characteristics of pediatric patients with Nager acrofacial dysostosis. Design:: Retrospective case series. Setting:: Multidisciplinary clinic in a tertiary care children''s hospital. Subjects:: Patients less than 18 years of age with Nager acrofacial dysostosis. Methods:: Nager syndrome is a mandibulofacial dysostosis associated with preaxial limb abnormalities and multiple craniofacial anomalies. Ten patients with Nager syndrome were reviewed. Relevant literature, 1966 to the present, was reviewed with the assistance of Medline. Results:: External and middle ear abnormalities are common in Nager syndrome. All non-atretic ears had significant difficulty with otitis media, requiring an average of two sets of tympanostomy tubes. Cholesteatoma was diagnosed in one patient. Pure conductive hearing loss was identified in eight patients with mixed hearing loss noted in two patients. Conductive hearing loss greater than 30dB HL was noted in 90% (9/10) of patients, with 40% (4/10) having 55–70dB HL loss. Although amplification was effective, results of surgical interventions to correct conductive hearing loss were inconsistent. Two patients with mixed hearing loss developed the sensorineural component in later childhood, indicating that progressive or fluctuating sensorineural hearing loss is also possible in this population. Conclusions:: Pediatric patients with Nager acrofacial dysostosis exhibit conductive hearing loss due to middle and external ear pathology. Prolonged ventilation of the middle ear via tympanostomy tubes and amplification with hearing aids are often required. Some patients also demonstrate mixed hearing loss that may be progressive and should be monitored carefully. Early and aggressive management in a multidisciplinary team approach is recommended. [Copyright &y& Elsevier]

Abstract: In our case report and literature review, we report about a female newborn with severe asphyxiating thoracic dysplasia of the spondylocostal dysostosis classification to whom an expandable thoracoplasty with metal implants offered survival and discharge at home from newborn to infancy. [Copyright &y& Elsevier]

Summary: We describe 2 patients with segmental costovertebral malformation, a form of spondylocostal dysostosis, associated with tethering of the conus to a lipomyelomeningocoele. Such an association is rare. In both these patients the defects occurred sporadically. The relevant literature is reviewed. [Copyright &y& Elsevier]

Background Acrodysostosis is a rare syndrome characterized by peripheral dysostosis, nasal hypoplasia, and frequently mental retardation. Only two adult cases of acrodysostosis have been reported to have neurological symptoms. Case Description We report one additional adult case that presented with signs of spinal cord compression from spinal stenosis, and make the first histologic description in the literature of the bony anomalies seen in acrodysostosis. The patient had a T3 to T5 laminectomy and experienced a complete recovery. Conclusions Special attention should be given to these patients to detect signs of spinal stenosis, as early decompression can lead to neurological recovery. [ABSTRACT FROM AUTHOR]