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Polyamines serve a number of vital functions in humans, including regulation of cellular proliferation, intracellular signaling, and modulation of ion channels. Ornithine decarboxylase 1 (ODC1) is the rate-limiting enzyme in endogenous polyamine synthesis. In this report, we present four patients with a distinct neurometabolic disorder associated with de novo heterozygous, gain-of-function variants in the ODC1 gene. This disorder presents with global developmental delay, ectodermal abnormalities including alopecia, absolute or relative macrocephaly, and characteristic facial dysmorphisms. Neuroimaging variably demonstrates white matter abnormalities, prominent Virchow-Robin spaces, periventricular cysts, and abnormalities of the corpus callosum. Plasma clinical metabolomics analysis demonstrates elevation of N-acetylputrescine, the acetylated form of putrescine, with otherwise normal polyamine levels. Therapies aimed at reducing putrescine levels, including ODC1 inhibitors, dietary interventions, and antibiotics to reduce polyamine production by gastrointestinal flora could be considered as disease-modifying therapies. As the ODC1 gene has been implicated in neoplasia, cancer surveillance may be important in this disorder., (© 2018 Wiley Periodicals, Inc.)

Disorders of brain formation can occur from pathogenic variants in various alpha and beta tubulin genes. Heterozygous pathogenic variants in the beta tubulin isotype A gene, TUBB2A, have been recently implicated in brain malformations, seizures, and developmental delay. Limited information is known regarding the phenotypic spectrum associated with pathogenic variants in this gene given the rarity of the condition. We report the sixth individual with a de novo heterozygous TUBB2A pathogenic variant, who presented with a severe neurological phenotype along with unique features of arthrogryposis multiplex congenita, optic nerve hypoplasia, dysmorphic facial features, and vocal cord paralysis, thereby expanding the gene-related phenotype., (© 2017 Wiley Periodicals, Inc.)

Lateral meningocele syndrome (LMS), or Lehman syndrome, is a rare disorder characterized by multiple lateral spinal meningoceles, distinctive facial features, joint hypermobility and hypotonia, along with skeletal, cardiac, and urogenital anomalies. Heterozygous NOTCH3 mutations affecting the terminal exon 33 were recently reported as causative in six families with LMS. We report a boy with LMS, the fourteenth reported case, with a de novo 80 base pair deletion in exon 33 of NOTCH3. Our patient's prenatal findings, complex cardiac anomalies, and severe feeding difficulties further expand our understanding of this rare condition., (© 2016 Wiley Periodicals, Inc.)

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by hypertelorism, bifid uvula, cleft palate and arterial tortuosity. We report on a patient with LDS, bearing mutation in the TGFβR2 gene, whose prenatal examination demonstrated clenched fists and club feet, suggesting arthrogryposis multiplex congenita. Postnatal assessment showed digital abnormalities, including brachydactyly, camptodactyly, partial syndactyly and absent distal phalanges. With the lack of fibrillin-1 microfibril deposition as well as impaired and inadequate elastic fiber assembly in our patient's fibroblasts, we speculate that the skeletal abnormalities seen in this patient with LDS are the result of lack of these components in embryonal perichondrium and in blood vessels. We suggest that LDS should be included in the differential diagnosis of joint contractures seen pre and postnatally. Prenatal diagnosis of LDS would be important in parental counseling and early post natal diagnosis could prompt treatment before the development of detrimental vascular complications., (© 2013 Wiley Periodicals, Inc.)

We report on a 46,XY female with pontocerebellar hypoplasia and intellectual disability. To our knowledge, this is the fourth reported patient with this constellation and further confirms a rare new syndrome. The condition is probably a single gene disorder with a currently unknown mode of inheritance. The causative gene is likely involved in the normal gonadal sex determination as well as the cerebral and cerebellar formation and function., (Copyright © 2013 Wiley Periodicals, Inc.)

Complex II deficiency is a rare cause of mitochondrial respiratory chain defects with a prevalence of 2-23%. It is exclusively nuclear encoded and functions in the citric acid cycle by oxidizing succinate to fumarate and in the mitochondrial electron transport chain (ETC) by transferring electrons to ubiquinone. Of the four subunits, SDHA and SDHB are catalytic and SDHC and SDHD are anchoring. Mutations in SDHA and SDHAF1 (assembly factor) have been found in patients with CII deficiency and a mitochondrial phenotype. We present a patient with CII deficiency with a previously undescribed phenotype of dilated cardiomyopathy, left ventricular noncompaction, failure to thrive, hypotonia, and developmental delay. Also, a comprehensive review of 36 cases published in the literature was undertaken. The results show that CII deficiency has a variable phenotype with no correlation with residual complex activity in muscle although the phenotype and enzyme activities are comparable within a family. For some, the condition was fatal in infancy, others had multisystem involvement and some had onset in adulthood with mild symptoms and normal cognition. Neurological involvement is most commonly observed and brain imaging commonly shows leukoencephalopathy, Leigh syndrome, or cerebellar atrophy. Mutations in SDHAF1 are associated with leukoencephalopathy. Other organ systems like heart, muscle, and eyes are only involved in about 50% of the cases but cardiomyopathy is associated with high mortality and morbidity. In some patients, riboflavin has provided clinical improvement., (Copyright © 2013 Wiley Periodicals, Inc.)

We report on a child with prenatal onset of overgrowth associated with thick, excessive wrinkled skin and other abnormalities including cleft palate, Chiari malformation and polymicrogyria. His clinical features do not resemble any of the known reported overgrowth syndromes. Genetic evaluations, including karyotype, oligoarray, methylation-sensitive multiplex ligation-dependent probe amplification (MLPA) for 11p11.2 region, CDKN1C sequencing, GPC3 sequencing and dosage analysis, and HRAS sequencing, have been un-revealing. Immunohistochemistry done on the patient's cultured skin fibroblasts showed normally assembled elastic fibers and normal pattern of chondroitin sulfate deposition with defective deposition of Collagen I fibers. In addition, there were high levels of immuno-detectable metalloproteinase 3 (MMP3) and undetectable tissue inhibitor of metalloproteinase 1 (TIMP1). The defective collagen deposition in the fibroblast culture could be reversed by the broad spectrum MMP inhibitor, doxycycline. We also present evidence that the fibroblasts of this patient have an increased rate of cellular proliferation. We propose that this is a previously unrecognized overgrowth syndrome associated with increased cellular proliferation and defective collagen I deposition due to an imbalance between MMP and TIMP in fibroblasts., (Copyright © 2012 Wiley Periodicals, Inc.)

Hearing impairment is common in individuals with branchio-oculo-facial (BOF) syndrome. The majority of described individuals have conductive hearing impairment due to malformed ossicles and/or external canal stenosis or atresia, although a sensorineural component to the hearing impairment in BOF syndrome is increasingly being reported. Sophisticated computed tomography (CT) of the temporal bone has revealed middle and inner ear malformations in three previous reports. We present middle and inner ear abnormalities in three additional individuals with mutation-proven BOF syndrome. We suggest that temporal bone CT imaging be included in the medical workup of a child with BOF syndrome, in order to guide management., (Copyright © 2012 Wiley Periodicals, Inc.)

We report on a consanguineous, Afghani family with two sisters affected with characteristic facial features, multiple contractures, progressive joint and skin laxity, hemorrhagic diathesis following minor trauma and multisystem fragility-related manifestations suggestive of a diagnosis of musculocontractural Ehlers-Danlos syndrome (EDS). This novel form of connective tissue disorder was recently reported in patients of Japanese, Turkish, and Indian descent who were formerly classified as having EDS type VIB and has now been recognized to be a part of spectrum including patients previously classified as having adducted thumb-clubfoot syndrome. We identified a previously unreported mutation in the CHST14 gene, which codes for the enzyme dermatan 4-O-sulfotransferase. We discuss the prenatal presentation, detailed clinical manifestations, and neurological findings in two sisters with this newly described musculocontractural EDS-CHST14 type. We demonstrate that fibroblasts from one of our patients produce more chondroitin sulfate than normal and show lower than normal deposition of collagens I and II and fibrillin 1-containing microfibrills. These findings suggest that the imbalance in the glycosaminoglycan content in developing tissues might interfere with normal deposition of other extracellular matrix components and ultimately contribute to the development of the phenotype observed in these patients. Furthermore, we ruled out the contribution of intrinsic platelet factors to the bleeding diathesis observed in some affected individuals., (Copyright © 2012 Wiley Periodicals, Inc.)

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with variability in clinical manifestations and molecular causes. In most cases, patients with BWS have normal development. Cases with developmental delay are usually attributed to neonatal hypoglycemia or chromosome abnormalities involving copy number variation for genes beyond the critical BWS region at 11p15.5. Brain abnormalities have not previously been recognized within the BWS phenotypic spectrum. We report on seven cases of BWS associated with posterior fossa abnormalities. Of these, two cases presented with Blake's pouch cyst, two with Dandy-Walker variant (DWV; hypoplasia of the inferior part of the vermis), one with Dandy-Walker malformation (DWM) and one with a complex of DWM, dysgenesis of the corpus callosum and brain stem abnormality. In all these cases, molecular findings involved the centromeric imprinted domain on chromosome locus 11p15.5, which includes imprinting center 2 (IC2) and the imprinted growth suppressor gene, CDKN1C. Three cases had loss of methylation at IC2, two had CDKN1C mutations, and one had loss of methylation at IC2 and a microdeletion. In one case no mutation/methylation abnormality was detected. These findings together with previously reported correlations suggest that genes in imprinted domain 2 at 11p15.5 are involved in normal midline development of several organs including the brain. Our data suggest that brain malformations may present as a finding within the BWS phenotype when the molecular etiology involves imprinted domain 2. Brain imaging may be useful in identifying such malformations in individuals with BWS and neurodevelopmental issues., (Copyright © 2012 Wiley Periodicals, Inc.)

Timothy syndrome (TS) is an autosomal dominant condition with the constellation of features including prolonged QT interval, hand and foot abnormalities, and mental retardation or autism. Splawski et al. [2004] previously described two phenotypes associated with TS distinguished by two unique and different mutations within the CACNA1C gene. We report on a newborn who presented with prolonged QT interval and associated polymorphic ventricular tachycardia, dysmorphic facial features, syndactyly of the hands and feet, and joint contractures, suggestive of TS. He developed a stroke, subsequent intractable seizures, and was found to have cortical blindness and later profound developmental delay. Initial targeted mutation analysis did not identify either of the previously described TS associated mutations; however, full gene sequencing detected a novel CACNA1C gene mutation (p.Ala1473Gly). The clinical and genetic findings in our case expand both the clinical and molecular knowledge of TS., (Copyright © 2011 Wiley Periodicals, Inc.)

We report on the third case of cutis laxa and progeroid features caused by a homozygous mutation in ALDH18A1 that encodes Δ¹-pyrroline-5-carboxylate-synthase (P5CS). This severely affected child, born to consanguineous parents of Pakistani origin, presented with lax, wrinkled and thin skin with dilated and tortuous subcutaneous blood vessels, corneal clouding, and hypotonia. The child had severe global developmental delay and feeding difficulties and died in infancy for an unknown reason. The proband was homozygous for a mutation in ALDH18A1, c.1923 + 1G > A which results in the production of two anomalous transcripts that are predicted to encode proteins lacking the catalytic site for the enzyme. The cellular phenotype is characterized by diminished production of collagen types I and III, altered elastin ultrastructure, and diminished cell proliferation of cultured dermal fibroblasts. This severe clinical and cellular phenotype overlaps with a broad group of neurocutaneous syndromes that include cutis laxa type II, wrinkly skin syndrome, de Barsy syndrome, and gerodermia osteodysplastica. The findings presented here emphasize the pleiotropic presentation of this group of conditions and suggest that multiple components of the extracellular matrix are perturbed in these disorders., (Copyright © 2011 Wiley-Liss, Inc.)

We have identified by microarray-based comparative genomic hybridization analysis (aCGH), a homozygous deletion of 8q24.3 [arr cgh 8q24.3(140,879,937 --> 141,021,392)x0 mat pat] in a patient with dysmorphic facial features, dysgenesis of the corpus callosum, and severe mental retardation. The deletion was inherited from asymptomatic, consanguineous parents, each of them being heterozygous for the same deletion. The only gene known to map to this segment is the NIBP gene, and so far no clinical manifestations have been found in association with this gene mutation in homozygous or heterozygous state in humans. Our findings suggest that a homozygous deletion in the NIBP gene results in an autosomal recessive condition with multiple abnormalities and severe delay. In addition, the child inherited a 781-kb deletion on 4q32.2 from the mother that contains the SPOCK3 gene. We suggest that this heterozygous deletion is likely to be non-contributory to the phenotype., (Copyright 2010 Wiley-Liss, Inc.)

Pelizaeus-Merzbacher disease (PMD) is a rare dysmyelination disorder, characterized by significant developmental delay, truncal hypotonia, spasticity, dysarthria, and nystagmus. Conventional magnetic resonance (MR) images demonstrate discordance of myelin maturation, while newer MR techniques, such as MR spectroscopy and diffusion tensor imaging, may be helpful in disease assessment. We report on a family of two young boys and their mother who share the same unusual 4-bp deletion of the PLP1 gene: c51_54 del TTCC, causing truncation of the PLP1 in exon 2. The brain MRI appearances in this unique deletion, using newer MR imaging, are described., ((c) 2010 Wiley-Liss, Inc.)

Raine syndrome is an autosomal recessive condition with generalized osteosclerosis, characteristic facial dysmorphism and brain abnormalities including intracerebral calcifications. We report on a case with Raine syndrome born to nonconsanguineous couple and report the prenatal sonogram/MRI, the fetopathology, and neuropathology findings., ((c) 2007 Wiley-Liss, Inc.)

The combination of pulmonary agenesis/dysgenesis/hypoplasia, microphthalmia/anophthalmia, and a diaphragmatic defect (agenesis or eventration) is a rare syndrome presumed to have an autosomal recessive mode of inheritance based on a report of affected siblings born to unaffected parents [Seller et al., 1996]. The condition is known as Spear syndrome and Matthew-Wood syndrome, although genetic heterogeneity cannot be ruled out. We report on eight patients with this condition including a living child, three sibs and three isolated cases. Most presented with fetal ultrasound findings of microphthalmia/anophthalmia, and diaphragmatic eventration/hernia and in five, cardiac abnormalities were also found. The earliest detection was at 20 weeks gestation. This is the second report of sibs affected with this condition, which supports an autosomal recessive mode of inheritance. We present the first and only reported living patient with this condition and expand the intrafamilial, interfamilial, and ethnic variability of this condition. We suggest changing the condition's name to PDAC to reflect the most important components of this condition.

Cobalamin-C (cblC) disease is a rare autosomal recessive disorder due to defective intracellular cobalamin metabolism. There are few (13) reported patients of the late-onset presentation of cblC disease with paucity of detailed clinical descriptions. This results in this condition being easily missed. In this report, we describe clinical and biochemical findings of two unrelated patients with late-onset cblC disease who presented with neuropsychiatric symptoms. Serial MRI images are provided for one of these patients. Presumptive diagnosis was made with urine and plasma biochemical markers and confirmed with fibroblast analysis. These patients illustrate the challenging diagnosis of this disease and also report on the rare associated findings of vasculopathy and mitochondrial respiratory chain dysfunction. Mutation analysis of the MMACHC gene showed that both patients were homozygous for 394C --> T which suggests a founder effect.

A T-to-C missense mutation at nucleotide position 9,185 in the protein-coding ATP6 gene of the mitochondrial genome was present at high heteroplasmy in members of a Canadian family with Leigh syndrome with predominant ataxia and peripheral neuropathy. This mutation results in the substitution of a proline residue for an evolutionary-conserved leucine at position of amino acid 220 near the carboxyl terminus of the mitochondrial protein. The index patient and brother, who had an identical clinical presentation, had >90% mutant mtDNA in cultured skin fibroblasts, lymphocytes, and whole blood. Their mother and a maternal uncle, symptomatic with a peripheral neuropathy alone, had 86% and 85% heteroplasmy, respectively. Symptomatic maternal cousins with early onset revealed 90% and 91% mutant mtDNA in all tissues analyzed. Studies of lymphoblasts from the asymptomatic maternal grandmother and eldest brother of the proband were heteroplasmic for mutant mtDNA with 56% and 17%, respectively. Biochemical analysis demonstrated normal respiratory chain enzyme activity in muscle and fibroblasts, normal ATP synthesis, but reduced oligomycin-sensitive H(+)ATPase in cultured lymphoblast mitochondria. We propose that the 9,185T > C mtDNA mutation is pathogenic even though the initial phenotype is mild and the biochemical phenotype not easily detectable., (Copyright 2007 Wiley-Liss, Inc.)