The genetic basis of DOORS syndrome: an exome-sequencing study.

BACKGROUND: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals. METHODS: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR. FINDINGS: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis. INTERPRETATION: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24. FUNDING: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.

A new case of a LUMBAR syndrome.

LUMBAR syndrome (lower body congenital infantile hemangiomas and other skin defects; urogenital anomalies and ulceration; myelopathy; bony deformities; anorectal malformations and arterial anomalies; and rectal anomalies) is a rare association between infantile hemangiomas of the lower half of the body and regional congenital anomalies. Since 1986, 53 cases have been reported and no etiology has been identified. We report on the 54th case in a male infant and review the literature concerning the manifestations of the LUMBAR syndrome.

Duplication of C7orf58, WNT16 and FAM3C in an obese female with a t(7;22)(q32.1;q11.2) chromosomal translocation and clinical features resembling Coffin-Siris Syndrome.

We characterized the t(7;22)(q32;q11.2) chromosomal translocation in an obese female with coarse features, short stature, developmental delay and a hypoplastic fifth digit. While these clinical features suggest Coffin-Siris Syndrome (CSS), we excluded a CSS diagnosis by exome sequencing based on the absence of deleterious mutations in six chromatin-remodeling genes recently shown to cause CSS. Thus, molecular characterization of her translocation could delineate genes that underlie other syndromes resembling CSS. Comparative genomic hybridization microarrays revealed on chromosome 7 the duplication of a 434,682 bp region that included the tail end of an uncharacterized gene termed C7orf58 (also called CPED1) and spanned the entire WNT16 and FAM3C genes. Because the translocation breakpoint on chromosome 22 did not disrupt any apparent gene, her disorder was deemed to result from the rearrangement on chromosome 7. Mapping of yeast and bacterial artificial chromosome clones by fluorescent in situ hybridization on chromosome spreads from this patient showed that the duplicated region and all three genes within it were located on both derivative chromosomes 7 and 22. Furthermore, DNA sequencing of exons and splice junctional regions from C7orf58, WNT16 and FAM3C revealed the presence of potential splice site and promoter mutations, thereby augmenting the detrimental effect of the duplicated genes. Hence, dysregulation and/or disruptions of C7orf58, WNT16 and FAM3C underlie the phenotype of this patient, serve as candidate genes for other individuals with similar clinical features and could provide insights into the physiological role of the novel gene C7orf58.

Tissue-limited mosaicism for monosomy 13.

Karyotypic discordance between different tissues in an individual is uncommon. We report on a patient with multiple congenital anomalies and mosaicism for monosomy 13 limited to fibroblasts. Findings include microcephaly, agenesis of the corpus callosum, bilateral posterior colobomas, cataract and optic nerve dysplasia, patent foramen ovale, renal hypoplasia, hypospadias and unilateral inguinal hernia, unilateral hypoplasia of the lower limb, sparse and patchy hair, subtle pigmentary mosaicism, and global developmental delay. The lymphocyte karyotype was normal, whereas the fibroblast karyotype showed mosaicism for a del(13)(q11→ter). Review of the literature identified three previous reports of similar patients with multiple congenital anomalies, normal lymphocyte karyotype, and subsequent, diagnostic fibroblast karyotyping. Comparison of the previously reported patients with the patient reported here defines a common phenotype for tissue-limited mosaicism for monosomy 13 consisting of prenatal-onset growth deficiency; microcephaly; facial abnormalities including prominent nasal bridge, hypertelorism, ptosis, epicanthal folds, microphthalmia, coloboma, retinoblastoma, prominent maxilla, micrognathia, and low-set ears; limb abnormalities including small to absent thumbs, clinodactyly of fifth finger, fused metacarpal bones 4 and 5, talipes equinovarus, and short first toe; cardiac defect; renal anomalies; and genitalia abnormalities including hypospadias and cryptorchidism. In conclusion, this case further emphasizes that fibroblast karyotyping should be employed when the diagnosis remains unclear, especially in the presence of pigmentary mosaicism or segmental hypoplasia.

Gardner-Silengo-Wachtel or genito-palato-cadiac syndrome with associated autosomal aneuploidy.

Gardner-Silengo-Wachtel or genito-palato-cardiac syndrome is a disorder of male (46,XY) gonadal dysgenesis, thought to be either an X-linked recessive or an autosomal recessive disorder. The propositus in our report presented with multiple congenital anomalies including micrognathia, cleft palate, congenital heart defect with D-transposition, double outlet right ventricle, PFO, VSD, PDA and pulmonary valve stenosis and gonadal dysgenesis. Chromosome analysis showed a 46, XY, t(1;7)(q32,q22.1) der(10) t(3;10) (q21;q26)pat karyotype. This represents a rare case of autosomal aneuploidy associated with Gardner-Silengo-Wachtel or genito-palato-cardiac syndrome and suggests genetic heterogeneity for this syndrome. Partial monosomy of 10q also shares many of the prominent features of genito-palato-cardiac syndrome, including gonadal dysgenesis, cardiac defects and facial features. Monosomy for distal 10q may present as a phenocopy of Gardner-Silengo-Wachtel or genito-palato-cardiac syndrome. Alternatively, unmasking of a recessive allele on distal 10q may result in genito-palato-cardiac syndrome, thus potentially localizing a candidate region for the gene to 10q26 --> qter.

DOOR syndrome: clinical report, literature review and discussion of natural history.

DOOR syndrome (deafness, onychodystrophy, osteodystrophy, and mental retardation) is a rarely described disorder with less than 35 reports in the literature. The hallmarks of the syndrome, represented in the DOOR acronym, include sensorineural hearing loss, hypoplastic or absent nails on the hands and feet, small or absent distal phalanges of the hands and feet, and mental retardation. The purpose of our communication is to report on an additional patient with DOOR syndrome, delineate common as well as less frequent manifestations of DOOR syndrome, bring attention to the under appreciated facial features in DOOR syndrome, document the natural history of this disorder, and propose a suggested workup of those suspected of DOOR syndrome. DOOR syndrome is associated with characteristic, coarse facial features with large nose with wide nasal bridge, bulbous tip and anteverted nares, a long prominent philtrum and downturned corners of the mouth. The natural history is one of a deteriorative course, with progressive neurological manifestations including sensorineural deafness, seizures from infancy, optic atrophy, and a peripheral polyneuropathy. The majority of patients with DOOR syndrome have elevated levels of 2-oxoglutarate in the urine and plasma. In this report, we present a newborn with manifestations consistent with DOOR syndrome and a progressive clinical course. A comprehensive literature review reveals 32 patients with DOOR syndrome. In conclusion, DOOR syndrome is a neurometabolic disorder with recognizable facial features and a progressive natural history.

Bifid tongue: a rare feature associated with infants of diabetic mother syndrome.

Infants born to diabetic mothers (IDM) are well documented to have a higher rate of congenital malformations. Sacral agenesis/hypogenesis and caudal dysgenesis are classically linked to maternal diabetes, but many other types of anomalies are more frequent. In this case report, we describe a male infant born to a diabetic mother who in addition to other typical congenital abnormalities was born with an impressive bifid tongue. Accompanying congenital anomalies include unilateral microphthalmia, bilateral microtia, cleft palate, micropenis with unilateral cryptorchidism, bilateral radial hypoplasia, unilateral pre-axial polydactyly, and mid-line central nervous system defects including arhinencephaly and pituitary hypoplasia. Review of the literature reveals an additional case of an infant with a bifid tongue born to a diabetic mother [Comess et al., 1969]. In conclusion, bifid tongue without oral hamartoma, a rare congenital anomaly, can be an associated finding in IDM.

Marinesco-Sjögren syndrome in a male with mild dysmorphism.

Marinesco-Sjogren syndrome (MSS) is a rare, autosomal recessive disorder comprising cataracts, cerebellar ataxia caused by cerebellar hypoplasia, mild to moderate mental retardation, neuromuscular weakness, short stature, hypergonadotrophic hypogonadism, and skeletal anomalies. The syndrome was recently mapped to chromosome 5q31, but there is evidence for genetic heterogeneity, and no gene has been identified. We report a 5-year-old male with cataracts, ataxia, a progressive cerebellar atrophy, developmental delay, seizures, hypotonia, and a sensorimotor neuropathy consistent with many cases of MSS. He also had mild craniofacial dysmorphism consisting of hypertrichosis and synophrys, deep-set eyes with epicanthic folds, a flat philtrum, a high palate, short thumbs, and a wide sandal gap between the first and second toes. Skeletal findings included an increased kyphosis. We reviewed the literature on MSS to determine if craniofacial dysmorphism and the presence of neuropathy and/or myopathy would prove to be diagnostically useful in this phenotypically heterogeneous condition. The majority of cases of MSS do not have craniofacial dysmorphism, but other cases have been reported with features such as ptosis or a myopathic facies that are likely to reflect the underlying myopathic or neuromuscular processes in MSS.

Fertility in a female with mosaic trisomy 8.

OBJECTIVE: To describe the first term pregnancy in a patient with the characteristic features of trisomy 8 mosaicism. DESIGN: Case report. SETTING: University department. PATIENT(S): The 23-year-old proband had a history of cleft palate, mixed bilateral hearing loss, short stature, and developmental delay. She had dysmorphic craniofacial features, mild musculoskeletal abnormalities, and abnormal skin pigmentation. Her karyotype was mos47,XX,+8[17]/46,XX[83]. INTERVENTION(S): Cytogenetic analysis and genetics evaluation of the proband and her child. MAIN OUTCOME MEASURE(S): The first successful pregnancy in a phenotypically abnormal trisomy 8 patient. RESULT(S): The pregnancy was largely uncomplicated except for an abnormal triple screen, with subsequent normal amniocentesis, and a fetal ultrasound revealing a clubfoot anomaly. Cytogenetic analysis of the child showed a 46,XX karyotype. CONCLUSION(S): Our review indicates that reproduction in females with mosaic trisomy 8 is possible, albeit uncommon. Until additional cases are reported and any specific risks identified, prenatal diagnosis of any pregnancies in mosaic trisomy 8 patients would seem prudent. In addition, this and previous cases illustrate the need to effectively counsel families of mosaic trisomy 8 children about the possibility of reproduction.

Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly.

Holoprosencephaly (HPE) is the most commonly occurring congenital structural forebrain anomaly in humans. HPE is associated with mental retardation and craniofacial malformations. The genetic causes of HPE have recently begun to be identified, and we have previously shown that HPE can be caused by haploinsufficiency for SONIC HEDGEHOG ( SHH). We hypothesize that mutations in genes encoding other components of the SHH signaling pathway could also be associated with HPE. PATCHED-1 (PTCH), the receptor for SHH, normally acts to repress SHH signaling. This repression is relieved when SHH binds to PTCH. We analyzed PTCH as a candidate gene for HPE. Four different mutations in PTCHwere detected in five unrelated affected individuals. We predict that by enhancing the repressive activity of PTCH on the SHH pathway, these mutations cause decreased SHH signaling, and HPE results. The mutations could affect the ability of PTCH to bind SHH or perturb the intracellular interactions of PTCH with other proteins involved in SHH signaling. These findings further demonstrate the genetic heterogeneity associated with HPE, as well as showing that mutations in different components of a single signaling pathway can result in the same clinical condition.