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Cleidocranial dysplasia (CCD) is a rare hereditary disease of unknown etiology which was previously known as cleidocranial dysostosis. It usually follows an autosomal dominant mode of transmission with no predilection of genre or ethnic group. It is caused by a mutation of RUNX2, characterized by generalized dysplasia of the bones and teeth. Affected individuals have short stature, atypical facial features, and skeletal anomalies affecting mainly the skull and clavicle. The dental manifestations are mainly delayed exfoliation of the primary teeth and delayed eruption of the permanent teeth, with multiple impacted supernumeraries, and the absence of cellular cementum. The frequency of this disorder is 1 per million individuals. Here we report a rare case of CCD in a 23 year old female patient having most of the characteristic features of this syndrome.

Cleidocranial dysplasia (CCD) is a rare hereditary disease of unknown etiology which was previously known as cleidocranial dysostosis. It usually follows an autosomal dominant mode of transmission with no predilection of genre or ethnic group. It is caused by a mutation of RUNX2, characterized by generalized dysplasia of the bones and teeth. Affected individuals have short stature, atypical facial features, and skeletal anomalies affecting mainly the skull and clavicle. The dental manifestations are mainly delayed exfoliation of the primary teeth and delayed eruption of the permanent teeth, with multiple impacted supernumeraries, and the absence of cellular cementum. The frequency of this disorder is 1 per million individuals. Here we report a rare case of CCD in a 23 year old female patient having most of the characteristic features of this syndrome. [ABSTRACT FROM AUTHOR]

To evaluate the relationship between prenatal ultrasonography (USG) and fetal autopsy findings. Among 453 pregnancy terminations performed because of fetal anomalies on prenatal USG, 54 with skeletal dysplasia on fetal autopsy were included in this retrospective study. The most common diagnoses among the 54 fetal autopsies were osteogenesis imperfecta (n=12), dysostosis (n=10), achondroplasia (n=9), arthrogryposis (n=6), and thanatophoric dysplasia (n=6). The prenatal USG and fetal autopsy findings showed complete agreement in 35 cases (64.8%), partial agreement in nine cases (16.6%), and disagreement in 10 cases (18.5%). Fetal autopsy via perinatal pathology is essential for precise identification of the type of skeletal dysplasia; it should be routinely performed to confirm the diagnosis of prenatally detected fetal anomalies. Autopsy is vital for accurate prenatal diagnosis and the 'gold standard' technique for the identification of clinically important abnormalities. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type 2 is a congenital lysosomal disease characterized by iduronate-2-sulfatase deficiency, which leads to excessive accumulation of glycosaminoglycans in tissue. Dysostosis, which primarily involves decreased bone mineralization with morphological changes in the bone, is a major skeletal condition in mucopolysaccharidosis, but its pathophysiology is not well known. Here, we report a case of mucopolysaccharidosis type 2 diagnosed at the age of 2 years with longitudinal follow-up data for more than 15 years. Although the patient underwent bone marrow transplantation, the developmental quotient did not improve, and cranial hyperostosis progressed prominently with a faintly dilated perivascular space. Other dysostoses and contraction of the joints were observed but did not improve either.

The objective of our study is to estimate the frequency and types of the tarsal coalition in the populations of the Czech Lands, where this type of data is still missing. Examined skeletal collections belong to seven different sites and periods (from the Early Bronze Age through the Migration Period and Middle Ages until the 20th century). Tarsal coalition is hereditary abnormal bridging between two tarsal bones (mainly talus, calcaneus, and navicular) which would normally be separate bones. The bridging is caused by a type of connective tissue. Gross macroscopic analysis and comparison with clinical and archaeological literature were used to detect the signs of tarsal coalition. In some cases, the analysis was combined with the radiographic examination. A total of 267 individuals from the following locations were observed: Mikulovice, Kolín, Praha-Zličín, Sady-Špitálky, Trutmanice, Znojmo, and skeletons of recent cadavers from the Department of Anatomy, Faculty of Medicine, Masaryk University, Brno. Another 212 isolated tarsal bones from Brno ossuary material (dated to the 13th-18th century and currently deposited in the Department of Anatomy) were also studied. We estimated that the frequency of tarsal coalition (when individuals from all seven studied archaeological collections were pooled) was 5.6 %. The tarsal coalition frequencies for individual collections ranged between 2.3 % - 10.3 %. If the ossuary material was included in the total tarsal coalition frequency calculations (the number of individuals from the ossuary material was calculated as the minimum number of individuals), the tarsal coalition frequency was 6.1 %. In most of the cases, the calcaneonavicular coalition was detected. The findings may expand our overall understanding of tarsal coalition and stimulate further clinical research when looking for a causal link between tarsal coalition and orthopaedic diseases, such as painful, rigid flatfoot (fibular spastic flatfoot, tarsal synostosis, or dysostosis), and their possible secondary complications (intra-articular trauma, infection, arthropathy, osteonecrosis, neoplasm). [ABSTRACT FROM AUTHOR]

Skeletal dysplasia encompasses a heterogeneous group of over 400 genetic disorders. They are individually rare, but collectively rather common with an approximate incidence of 1/5000. Thus, radiologists occasionally encounter skeletal dysplasias in their daily practices, and the topic is commonly brought up in radiology board examinations across the world. However, many radiologists and trainees struggle with this issue because of the lack of proper resources. The radiological diagnosis of skeletal dysplasias primarily rests on pattern recognition—a method that is often called the "Aunt Minnie" approach. Most skeletal dysplasias have an identifiable pattern of skeletal changes composed of unique findings and even pathognomonic findings. Thus, skeletal dysplasias are the best example to which the Aunt Minnie approach is readily applicable. [ABSTRACT FROM AUTHOR]

Crouzon syndrome is a rare genetic disorder. We report a rare case of Crouzon syndrome in a very young infant with distinct features of craniofacial malformations. A 10-week-old male child presented with features of craniofacial dysostosis with abnormal shape of the skull, proptosis, hypertelorism, curved nose and frontal bossing. Radiological findings revealed a predominant premature fusion of sagittal sutures. The infant had airway obstruction. Features of hydrocephalus, papilledema and optic atrophy were not evident. We chose to manage the symptoms and prevent complications, and the surgery was deferred for later, depending on the degree of malformation and psychological needs. Diagnosis of this rare condition at an early stage can help in preventing the development of complications. A careful follow-up and appropriate surgical intervention can improve the prognosis of this condition, which carries the risk of respiratory complications, poor vision and, in some cases, mental retardation as the age advances.

In 2019, the Nosology Committee of the International Skeletal Dysplasia Society provided an updated version of the Nosology and Classification of Genetic Skeletal Disorders. This is a reference list of recognized diseases in humans and their causal genes published to help clinician diagnosis and scientific research advances. Complementary to mammalian models, zebrafish has emerged as an interesting species to evaluate chemical treatments against these human skeletal disorders. Due to its versatility and the low cost of experiments, more than 80 models are currently available. In this article, we review the state-of-art of this “aquarium to bedside” approach describing the models according to the list provided by the Nosology Committee. With this, we intend to stimulate research in the appropriate direction to efficiently meet the actual needs of clinicians under the scope of the Nosology Committee.

In 2019, the Nosology Committee of the International Skeletal Dysplasia Society provided an updated version of the Nosology and Classification of Genetic Skeletal Disorders. This is a reference list of recognized diseases in humans and their causal genes published to help clinician diagnosis and scientific research advances. Complementary to mammalian models, zebrafish has emerged as an interesting species to evaluate chemical treatments against these human skeletal disorders. Due to its versatility and the low cost of experiments, more than 80 models are currently available. In this article, we review the state-of-art of this "aquarium to bedside" approach describing the models according to the list provided by the Nosology Committee. With this, we intend to stimulate research in the appropriate direction to efficiently meet the actual needs of clinicians under the scope of the Nosology Committee. [ABSTRACT FROM AUTHOR]

Background: Acrodysostosis is a rare hereditary disorder described as a primary bone dysplasia with or without hormonal resistance. Pathogenic variants in the PRKAR1A and PDE4D genes are known genetic causes of this condition. The latter gene variants are more frequently identified in patients with midfacial and nasal hypoplasia and neurological involvement. The aim of our study was to analyse and confirm a genetic cause of acrodysostosis in a male patient. Case presentation: We report on a 29-year-old Lithuanian man diagnosed with acrodysostosis type 2. The characteristic phenotype includes specific skeletal abnormalities, facial dysostosis, mild intellectual disability and metabolic syndrome. Using patient's DNA extracted from peripheral blood sample, the novel, likely pathogenic, heterozygous de novo variant NM_001104631.2:c.581G > C was identified in the gene PDE4D via Sanger sequencing. This variant causes amino acid change (NP_001098101.1:p.(Arg194Pro)) in the functionally relevant upstream conserved region 1 domain of PDE4D. Conclusions: This report further expands the knowledge of the consequences of missense variants in PDE4D that affect the upstream conserved region 1 regulatory domain and indicates that pathogenic variants of the gene PDE4D play an important role in the pathogenesis mechanism of acrodysostosis type 2 without significant hormonal resistance. [ABSTRACT FROM AUTHOR]

The musculoskeletal (MSK) system begins to form in the third week of intrauterine development. Multiple genes are involved in the complex different processes to form the skeleton, muscles and joints. The embryonic period, from the third to the eighth week of development, is critical for normal development and therefore the time when most structural defects are induced. Many of these defects have a genetic origin, but environmental factors may also play a very important role. This review summarizes the embryology of the different components of the MSK system and their configuration as an organ-system, analyzes the clinical implications resulting from failures in the process of organogenesis, and describes the first approach to diagnosis of skeletal abnormalities using prenatal ultrasound. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type I is inherited in an autosomal recessive manner and results from the defective activity of the enzyme alpha-L-iduronidase, which leads to the accumulation of glycosaminoglycans (mainly heparan and dermatan sulfate) in the lysosomes and further multiple organ dysfunction. This severe genetic progressive disease can be detected at an early age by skeletal deformities and phenotypic data. Early enzyme replacement therapy and/or bone marrow transplantation can slow down irreversible damages to various organs and systems or reduce their severity and improve the quality of life for a child.

A removable partial denture supported by resin-bonded precision attachments was constructed for a patient with intra oral symptoms of a cleidocranial dysostosis. Because of the anatomic situation, the youth, and the preprosthetic orthodontic treatment of the patient, a conventional prosthetic solution seemed inappropriate. Custom-made attachments were constructed with the spark erosion technique. They were fixed to the abutment teeth with resin-bonded retainers. The combination of the resin-bonding technique with the modern technology of spark erosion thus allowed a conservative approach to the oral rehabilitation of a young patient. [ABSTRACT FROM AUTHOR]

The article focuses on research regarding accessory jaw structures and teeth abnormalities. In cleidocranial dysostosis and cleft lip, incidence of multiple supernumerary teeth was found. Sporadic manifestations of supernumeraries occur mostly in the midline and molar regions of the maxilla, followed by the premolar region of the mandible. Researchers have concluded that double teeth result from either germination or fusion. Several individuals have been found to have both unilateral and bilateral hyperplasia and benign neoplasia of the coronoid process of the mandible.

The article focuses on the clinical and genetic considerations in craniofacial malformations. It is stated that oral manifestations of disorders of genetic origin can be illustrated in marked tissue changes of the craniofacial complex. It is believed that appropriate evaluation of the altered pattern of dental formation or dental appearance as well as tooth eruption irregularities may prove to be helpful in the diagnosis of an underlying genetic condition. Several researches have been conducted on the postnatal changes of the craniofacial complex in patients with various diseases of genetic origin, but it is stated that more information is required for better prognosis and treatment planning.

The article discusses the genetic factors that contribute to the development of occlusion. It cites that systemic conditions influence the development of the dentition and occlusion such as mandibular facial dysostosis, marfan syndrome, down syndrome, and anhydrotic ectodermal dysplasia. It cites that amelogenesis imperfecta, an autosomal dominant inherited hypocalcification of enamel, contributes to the heritable defects of enamel and dentin. Moreover, it mentions that the shovel shape of incisors may be due to genetic factors.

Introduction: Cleidocranial dysplasia (CCD) is an autosomal dominant disorder primarily affecting bones, which undergo membranous ossification. It commonly presents with significant dental and facial problems, including the hypoplastic maxilla, retained primary teeth, unerupted permanent teeth and supernumerary teeth. It is usually diagnosed based on clinical and radiographic findings, which are pathognomic. Here, we report clinical and radiographic findings of 7 patients with CCD who reported to our Institute during 2013-2014. Results: Age of patient ranged from 13 to 55 years, out of which 5 were males and 2 were females. Characteristic clinical findings, which were present in all cases include frontal and parietal bossing, brachycephalic skull, hypertelorism, broad nasal bridge and shoulder hypermobility. Radiographic findings seen were hypoplasia/aplasia of the clavicle, open skull suture, wide, open fontanel, and the presence of impacted permanent and supernumerary teeth. In one case, there was follicular cyst associated with impacted mandibular canine. Conclusion: Successful treatment involves a multidisciplinary approach and involves timely diagnosis at an early stage of development

The mucopolysaccharidoses are a heterogeneous group of inherited lysosomal storage disorders, characterized by the accumulation of undegraded glycosaminoglycans in various organs, leading to tissue damage. Mucopolysaccharidoses include eight individual disorders (IS [Scheie syndrome], IH [Hurler syndrome], II, III, IV, VI, VII and IX). They have autosomal-recessive transmission with the exception of mucopolysaccharidosis II, which is X-linked. Each individual disorder has a wide spectrum of phenotypic variation, depending on the specific mutation, from very mild to very severe. The skeletal and central nervous systems are particularly affected. The typical clinical presentation includes organomegaly, dysostosis multiplex with short trunk dwarfism, mental retardation and developmental delay. In this article, we review the neuroimaging manifestations of the different types of mucopolysaccharidoses including the dysostosis multiplex of the skull and spine as well as the various central nervous system complications. These include white matter injury, enlargement of the perivascular spaces, hydrocephalus, brain atrophy, characteristic enlargement of the subarachnoid spaces as well as compressive myelopathy. The correlation between several of the neuroimaging features and disease severity remains controversial, without well-established imaging biomarkers at this time. Imaging has, however, a crucial role in monitoring disease progression, in particular craniocervical junction stenosis, cord compression and hydrocephalus, because this allows for timely intervention before permanent damage occurs. [ABSTRACT FROM AUTHOR]

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]

Introduction. Patients with spondylocostal dysostosis (SCD) have congenital spine and rib deformities associated with frequently severe thoracic insufficiency and respiratory compromise. The literature is largely composed of case reports and small cohorts, and there is little information regarding adults with this condition. In this report, we describe the natural history of a conservatively treated patient and include quality-of-life issues such as childbearing, athletic participation, and occupational selection. Case Presentation. We present a patient with SCD who was conservatively treated by a single physician from birth for 31 years. Our patient was capable of a reasonably good quality of life through adulthood, including participation in gymnastics and employment. At age 18, she became pregnant and subsequently terminated the pregnancy due to obstetrical concerns for compromised respiration. She has had intermittent respiratory complaints and occasionally experiences dyspnea with exertion, but this only has limited her during certain activities in the past three years. Currently, she takes naproxen for chronic back pain with periodic exacerbations. Discussion. Other cases in the literature have described adult SCD patients who have received nonoperative treatment and achieved a wide range of functional outcomes. This provides some limited evidence to suggest that select patients with SCD may be treated conservatively and achieve a reasonable quality of life. However, close clinical follow-up with these patients is recommended, particularly early on, considering the high rates of infant morbidity and mortality. Chest physiotherapy and early pulmonary care have been associated with favorable outcomes in infancy. Surgery to increase thoracic volume and correct scoliosis has been shown in some cases to improve respiratory function. Treatment depends on the degree of thoracic insufficiency and quality of life. The natural history of SCD remains largely unknown, but some patients are capable of relatively favorable life spans, employment, and participation in athletics. [ABSTRACT FROM AUTHOR]

Aim: Mucopolysaccharidosis Type IVA (MPS IVA), Morquio A, is caused by the deficiency in lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase. Multisystemic involvements include skeletal systems, pulmonary disease, valvular heart disease, hearing loss, mild hepatomegaly, corneal clouding, coarse facial features. Materials and Methods: We retrospectively analyzed clinical and laboratory and follow up findings of our 25 patients with ministry for primary industries independent verification agency. Results: Mean age of the patients was 14.9±7.05 (5.5-36 years). Mean age at diagnosis was 7.3±6.2 years (6 months-31 years). Female: male ratio was 13/12. All patients had skeletal manifestation and X-ray analysis demonstrated "dysostosis multiplex". Twelve patients (48%) had cardiac valve disease. Twenty three (92%) patients had corneal clouding, 15 (60%) patients had hearing loss and 9 (36%) had hepatomegaly. Six (24%) patients were unable to walk. Mean follow up period is 7.4 years ±3.5 years (3 months-17 years). Four patients have not visit our clinical for last =3 years. Three patients died during follow up. Conclusion: MPS IVA is a severe disorder and is usually fatal in the second or third decade of life due to the complications of the disease. Early diagnosis of the patient became more important, because specific therapy with elasulphase alpha was approved recent years ago. [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]

Proximal 16p11.2 microdeletions are recurrent microdeletions with an overall prevalence of 0.03%. In patients with segmentation defects of the vertebra ( SDV), a burden of this microdeletion was observed with TBX6 as a candidate gene for SDV. In a published cohort of patients with congenital scoliosis ( CS), TBX6 haploinsufficiency was compound heterozygous with a common haplotype. Besides, a single three-generation family with spondylocostal dysostosis ( SCD) was reported with a heterozygous stop-loss of TBX6. These observations questioned both on the inheritance mode and on the variable expressivity associated with TBX6-associated SDV. Based on a national recruitment of 56 patients with SDV, we describe four patients with variable SDV ranging from CS to SCD associated with biallelic variations of TBX6. Two patients with CS were carrying a proximal 16p11.2 microdeletion associated with the previously reported haplotype. One patient with extensive SDV was carrying a proximal 16p11.2 microdeletion associated with a TBX6 rare missense change. One patient with a clinical diagnosis of SCD was compound heterozygous for two TBX6 rare missense changes. The three rare variants were affecting the chromatin-binding domain. Our data illustrate the variable expressivity of recessive TBX6 ranging from CS to SCD. [ABSTRACT FROM AUTHOR]

Ischiospinal Dysostosis (ISD) is a complex and very rare medical entity. It is associated with kyphoscoliosis, dysplasia or aplasia of the ischial rami, segmental anomalies of the bony vertebrae, and peculiar facial morphologies. In this case report, we present a child with Ischiospinal Dysostosis and Pierre-Robin Syndrome. This case report is unique as we followed the patient for 13 years in which he had multiple spinal procedures to treat his kyphoscoliosis. In this paper, we elucidated the number of case reports with documented follow-up regarding spinal cord injury or other complications of ISD and its management. [ABSTRACT FROM AUTHOR]

The article offers information on the Treacher Collins syndrome (TCS), a rare craniofacial morphogenesis that affect one in every 50,000 live births in Great Britain and the U.S. The topics discussed include the etiology and genetics of TCS, the different kinds of TCS, and the clinical manifestations of TCS.

The acrofacial dysostoses (AFD) are a genetically heterogeneous group of inherited disorders with craniofacial and limb abnormalities. Rodriguez syndrome is a severe, usually perinatal lethal AFD, characterized by severe retrognathia, oligodactyly and lower limb abnormalities. Rodriguez syndrome has been proposed to be a severe form of Nager syndrome, a non-lethal AFD that results from mutations in SF3B4, a component of the U2 small nuclear ribonucleoprotein particle (U2 snRNP). Furthermore, a case with a phenotype intermediate between Rodriguez and Nager syndromes has been shown to have an SF3B4 mutation. We identified heterozygosity for SF3B4 mutations in Rodriguez syndrome, confirming that the phenotype is a dominant disorder that is allelic with Nager syndrome. The mutations led to reduced SF3B4 synthesis and defects in mRNA splicing, primarily exon skipping. The mutations also led to reduced expression in growth plate chondrocytes of target genes, including the DLX5, DLX6, SOX9, and SOX6 transcription factor genes, which are known to be important for skeletal development. These data provide mechanistic insight toward understanding how SF3B4 mutations lead to the skeletal abnormalities observed in the acrofacial dysostoses. [ABSTRACT FROM AUTHOR]

Acromelic frontonasal dysostosis ( AFND) is a distinctive and rare frontonasal malformation that presents in combination with brain and limb abnormalities. A single recurrent heterozygous missense substitution in ZSWIM6, encoding a protein of unknown function, was previously shown to underlie this disorder in four unrelated cases. Here we describe four additional individuals from three families, comprising two sporadic subjects (one of whom had no limb malformation) and a mildly affected female with a severely affected son. In the latter family we demonstrate parental mosaicism through deep sequencing of DNA isolated from a variety of tissues, which each contain different levels of mutation. This has important implications for genetic counselling. [ABSTRACT FROM AUTHOR]

Background Miller syndrome (post-axial acrofacial dysostosis) arises from gene mutations for the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). Nonetheless, despite demonstrated loss of enzyme activity dihydroorotate (DHO) has not been shown to accumulate, but paradoxically urine orotate has been reported to be raised, confusing the metabolic diagnosis. Methods We analysed plasma and urine from a 4-year-old male Miller syndrome patient. DHODH mutations were determined by PCR and Sanger sequencing. Analysis of DHO and orotic acid (OA) in urine, plasma and blood-spot cards was performed using liquid chromatography-tandem mass spectrometry. In vitro stability of DHO in distilled water and control urine was assessed for up to 60 h. The patient received a 3-month trial of oral uridine for behavioural problems. Results The patient had early liver complications that are atypical of Miller syndrome. DHODH genotyping demonstrated compound-heterozygosity for frameshift and missense mutations. DHO was grossly raised in urine and plasma, and was detectable in dried spots of blood and plasma. OA was raised in urine but undetectable in plasma. DHO did not spontaneously degrade to OA. Uridine therapy did not appear to resolve behavioural problems during treatment, but it lowered plasma DHO. Conclusion This case with grossly raised plasma DHO represents the first biochemical confirmation of functional DHODH deficiency. DHO was also easily detectable in dried plasma and blood spots. We concluded that DHO oxidation to OA must occur enzymatically during renal secretion. This case resolved the biochemical conundrum in previous reports of Miller syndrome patients, and opened the possibility of rapid biochemical screening. [ABSTRACT FROM AUTHOR]

Sialidoses are autosomal recessive disorders caused by NEU1 gene mutations and are classified on the basis of their phenotype and onset age. Sialidosis type II, with infantile onset, has a more severe phenotype characterized by coarse facial features, hepatomegaly, dysostosis multiplex, and developmental delay while patients with the late and milder type, known as 'cherry red spot-myoclonus syndrome' develop myoclonic epilepsy, visual impairment and ataxia in the second or third decade of life. The diagnosis is usually suggested by increased urinary bound sialic acid excretion. We recently described genetically diagnosed patients with a specially mild phenotype, no retinal abnormalities and normal urinary sialic acid. This observation suggests that genetic analysis or the demonstration of the neuraminidase enzyme deficiency in cultured fibroblasts are needed to detect and diagnose mildest phenotypes. [ABSTRACT FROM AUTHOR]