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PubMed2000

Overlap of dyskeratosis congenita with the Hoyeraal-Hreidarsson syndrome.

X-linked dyskeratosis congenita (DKC) is characterized by mucosal leukoplakia and ulcerations, skin abnormalities, nail dystrophy, and pancytopenia. Hoyeraal-Hreidarsson syndrome (HHS) includes intrauterine growth retardation, microcephaly, mental retardation, cerebellar malformation, and pancytopenia. A patient with striking features of both HHS and DKC has a de novo mutation in the DKC1 gene, known to be responsible for DKC. HHS may be a severe form of DKC, in which affected individuals die before characteristic mucocutaneous features develop.

Cell Cycle Proteins↗

PubMed2002

Predictors of developmental disabilities after open heart surgery in young children with congenital heart defects.

OBJECTIVES: To determine the prevalence of persistent developmental impairments in children with congenital heart defects and to identify factors that enhance risk for an adverse outcome. STUDY DESIGN: Eligible infants (n = 131) <2 years of age requiring open heart surgery were recruited prospectively. Subjects were assessed during surgery and again 12 to 18 months later with standardized developmental assessments and formal neurologic examinations. RESULTS: Mean age at follow-up testing was 19.1 +/- 6.6 months. Assessments indicated that 41% had abnormal neurologic examinations. Gross and/or fine motor delays were documented in 42%, and 23% demonstrated global developmental delay. Univariate and multiple regression models identified the following factors increasing the risk for persistent developmental deficits: preoperative and acute postoperative neurodevelopmental status and microcephaly, type of heart lesion, length of deep hypothermic circulatory arrest, age at surgery, and days in the intensive care unit (P <.05). CONCLUSIONS: Children with congenital heart defects commonly have ongoing neurologic, motor, and developmental deficits well after surgical correction. The cause is multifactorial and includes brain injury before, during, and after heart surgery.

Abnormalities, Multiple↗

PubMed1971

Pathogenesis of H-1 virus infection of embryonic hamster bone in organ culture.

H-1 virus infection of hamsters has been shown to produce runting, microcephaly, cranial lacunae, and deformed teeth in animals inoculated during the suckling period and to cause various abnormalities, including skeletal defects, in embryos infected transplacentally. To explore the pathogenesis of these effects of viral infection on bone, the response of embryonic hamster tibiae in organ culture to inoculation with the H-1 strain of picodna virus was studied. This system made possible the direct observation of the reaction of bone to virus in a regulated environment. During a period of 7-17 days after inoculation the following observations were made: (a) H-1 virus was found to infect and replicate in bone. (b) Infected bones became more translucent, slender, and elongated than control bones. (c) Bone growth as measured by increase in wet weight was reduced in infected tibiae. (d) Infected bones showed periosteal and perichondral degeneration and diminished deposits of subperiosteal bone. It was concluded that the skeletal abnormalities which develop in embryonic and suckling hamsters after H-1 virus inoculation are the direct result of viral replication in bone, and that indirect phenomena such as those associated with chronic infection need not be postulated to explain the deformities seen in these animals.

Abnormalities, Multiple↗

PubMed2000

The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1.

We studied a large consanguineous Anatolian family with children who exhibited hydranencephaly associated with microcephaly. The children were severely affected. This novel genetic disorder is autosomal recessive. We used autozygosity mapping to identify a locus at chromosome 16p13.3-12.1; it has a LOD score of 4.11. The gene locus is within a maximal 11-cM interval between markers D16S497 and D16S672 and within a minimal critical region of 8 cM between markers D16S748 and D16S490.

Abnormalities, Multiple↗

PubMed2001

Large-scale deletions and SMADIP1 truncating mutations in syndromic Hirschsprung disease with involvement of midline structures.

Hirschsprung disease (HSCR) is a common malformation of neural-crest-derived enteric neurons that is frequently associated with other congenital abnormalities. The SMADIP1 gene recently has been recognized as disease causing in some patients with 2q22 chromosomal rearrangement, resulting in syndromic HSCR with mental retardation, with microcephaly, and with facial dysmorphism. We screened 19 patients with HSCR and mental retardation and eventually identified large-scale SMADIP1 deletions or truncating mutations in 8 of 19 patients. These results allow further delineation of the spectrum of malformations ascribed to SMADIP1 haploinsufficiency, which includes frequent features such as hypospadias and agenesis of the corpus callosum. Thus, SMADIP1, which encodes a transcriptional corepressor of Smad target genes, may play a role not only in the patterning of neural-crest-derived cells and of CNS but also in the development of midline structures in humans.

Abnormalities, Multiple↗

PubMed2001

Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features.

Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR). Patients with ZFHX1B deficiency typically show mental retardation, delayed motor development, epilepsy, microcephaly, distinct facial features, and/or congenital heart disease, in addition to the cardinal form of HSCR. To investigate the breadth of clinical variation, we studied DNA samples from six patients with clinical profiles quite similar to those described elsewhere for ZFHX1B deficiency, except that they did not have HSCR. The results showed the previously reported R695X mutation to be present in three cases, with three novel mutations-a 2-bp insertion (760insCA resulting in 254fs262X), a single-base deletion (270delG resulting in 91fs107X), and a 2-bp deletion (2178delTT resulting in 727fs754X)-newly identified in the other three. All mutations occurred in one allele and were de novo events. These results demonstrate that ZFHX1B deficiency is an autosomal dominant complex developmental disorder and that individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels.

Abnormalities, Multiple↗

PubMed2003

Cohen syndrome is caused by mutations in a novel gene, COH1, encoding a transmembrane protein with a presumed role in vesicle-mediated sorting and intracellular protein transport.

Cohen syndrome is an uncommon autosomal recessive disorder whose diagnosis is based on the clinical picture of nonprogressive psychomotor retardation and microcephaly, characteristic facial features, retinal dystrophy, and intermittent neutropenia. We have refined the critical region on chromosome 8q22 by haplotype analysis, and we report the characterization of a novel gene, COH1, that is mutated in patients with Cohen syndrome. The longest transcript (14,093 bp) is widely expressed and is transcribed from 62 exons that span a genomic region of approximately 864 kb. COH1 encodes a putative transmembrane protein of 4,022 amino acids, with a complex domain structure. Homology to the Saccharomyces cerevisiae VPS13 protein suggests a role for COH1 in vesicle-mediated sorting and transport of proteins within the cell.

Abnormalities, Multiple↗

PubMed1997

Genetic mapping using microcell-mediated chromosome transfer suggests a locus for Nijmegen breakage syndrome at chromosome 8q21-24.

Nijmegen breakage syndrome (NBS) is an autosomal recessive disorder characterized by microcephaly, short stature, immunodeficiency, and a high incidence of cancer. Cultured cells from NBS show chromosome instability, an increased sensitivity to radiation-induced cell killing, and an abnormal cell-cycle regulation after irradiation. Hitherto, patients with NBS have been divided into the two complementation groups V1 and V2, on the basis of restoration of radioresistant DNA synthesis, suggesting that each group arises from a different gene. However, the presence of genetic heterogeneity in NBS has been considered to be controversial. To localize the NBS gene, we have performed functional complementation assays using somatic cell fusion between NBS-V1 and NBS-V2 cells, on the basis of hyper-radiosensitivity, and then have performed a genomewide search for the NBS locus, using microcell-mediated chromosome transfer followed by complementation assays based on radiosensitivity. We found that radiation resistance was not restored in the fused NBS-V1 and NBS-V2 cells and that only human chromosome 8 complements the sensitivity to ionizing radiation, in NBS cell lines. In complementation assays performed after the transfer of a reduced chromosome, merely the long arm of chromosome 8 was sufficient for restoring the defect. Our results strongly suggest that NBS is a homogeneous disorder and that the gene for NBS is located at 8q21-24.

Abnormalities, Multiple↗

PubMed1993

Discordant phenotype of two overlapping deletions involving the PAX3 gene in chromosome 2q35.

Waardenburg syndrome (WS), the most common form of inherited congenital deafness, is a pleiotropic, autosomal dominant condition with variable penetrance and expressivity. WS is clinically and genetically heterogeneous. The basis for the phenotypic variability observed among and between WS families is unknown. However, mutations within the paired-box gene, PAX3, have been associated with a subset of WS patients. In this report we use cytogenetic and molecular genetic techniques to study a patient with WS type 3, a form of WS consisting of typical WS type 1 features plus mental retardation, microcephaly, and severe skeletal anomalies. Our results show that the WS3 patient has a de novo paternally derived deletion, del (2)(q35q36), that spans the genetic loci PAX3 and COL4A3. A molecular analysis of a chromosome 2 deletional mapping panel maps the PAX3 locus to 2q35 and suggests the locus order: centromere-(INHA, DES)-PAX3-COL4A3-(ALPI, CHRND)-telomere. Our analyses also show that a patient with a cleft palate and lip pits, but lacking diagnostic WS features, has a deletion, del (2)(q33q35), involving the PAX3 locus. This result suggests that not all PAX3 mutations are associated with a WS phenotype and that additional regional loci may modify or regulate the PAX3 locus and/or the development of a WS phenotype.

Bone and Bones↗

PubMed1994

Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome.

Forty-nine individuals have been identified with deletions or translocations involving the short arm of chromosome 5. While most display the classical phenotype of the cri-du-chat syndrome, several of the patients do not have the syndrome or have only a subset of the clinical features. Somatic cell hybrids containing the deleted chromosome 5 were derived from each patient. Each somatic cell hybrid was analyzed at the DNA level using 136 chromosome 5p-specific DNA fragments. It was possible to unambiguously order most of the chromosomal breakpoints present in the somatic cell hybrids based on the hybridization patterns of Southern blots. Further comparisons between the deletions present in the patients and their clinical features identified several chromosomal regions that were involved in specific clinical features. A critical chromosomal region involved the high-pitched cry mapped to 5p15.3, while the chromosomal region involved in the remaining features of the cri-du-chat syndrome mapped to a small region within 5p15.2. Deletions that did not include these two chromosomal regions presented varying clinical phenotypes from severe mental retardation and microcephaly to a clinically normal phenotype. These results demonstrate the need for careful characterization of a 5p deletion in prenatal cases before clinical predictions are made.

Animals↗

PubMed2006

Rotating distraction osteogenesis in a child with secondary craniosyntostosis.

Distraction osteogenesis has been acknowledged as a most effective surgical method to maximize intracranial space in patients with craniosynostosis by progressive displacement of the skull flap. However, it is difficult to control the growth direction of the skull flap even with application of four distraction bars. The authors of this study performed a cranioplasty procedure in a four-year-old girl with brachicephalic microcephaly, who showed a high lumbar puncture pressure of 21 cm H2O. After bilateral frontal craniectomy, the frontal bone and the midline of the superior orbital bone were fixed with a single wire, thus converting the linear displacement of distraction to a rotation flap and raising the skull flap superiorly. This rotational distraction osteogenesis resulted in a longer distance of distraction and upward rotation of the frontal skull flap with only two distraction bars. The authors suggest that rotating distraction osteogenesis has several merits: lesser depression of the bone flap, longer distance of distraction, and it is simpler and more economic than linear distraction. We also advocate that more aggressive surgical procedures should be considered for even older children with high intracranial pressure.

Bone Wires↗

PubMed1979

Lissencephaly (agyria) on computed tomography.

Unusual computed tomographic findings were observed in two infants with similar clinical pictures including delay in developmental milestones, seizures, decerebrated posture, and microcephaly. Computed tomography revealed small brain with widened subarachnoid space, smooth surface of the brain, uniformly enlarged ventricles, wide sylvian cisterns, and lack of insular opercularization. These findings coincide with pathologic features of lissencephaly (agyria), a rare congenital anomaly of the brain due to interruption of neuronal migration.

Brain↗

PubMed1997

Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome.

Cerebro-oculo-facial-skeletal (COFS) syndrome is a rare autosomal recessive disorder with microcephaly, severe mental retardation, and death in childhood. The pathogenesis is unknown. Neuropathological features of 8 children with COFS syndrome are presented. Seven of the children, ranging in age from 36 weeks gestation to 5 years 8 months, are of North American aboriginal background from Manitoba, Canada. The eight child is a 3-year-old Caucasian male. In all children there was severe microencephaly and mild ventriculomegaly. Cerebral myelination appeared to be delayed in one infantile case. Swollen ubiquitinated granular cells appeared in the white matter shortly after birth. Older children displayed cortical neuron loss, patchy or diffuse absence of myelin and gliosis in the white matter, and pericapillary and parenchymal mineralization in the globus pallidus and to a lesser extent the putamen and cerebral cortex. The cerebellum of older children exhibited severe degenerative changes involving the internal granular layer and Purkinje cell layer. The neuropathological changes, previously not well documented, suggest that COFS syndrome is associated with a degenerative process that begins in utero and affects many brain cell types. Similarities to Cockayne syndrome are discussed.

Brain↗

PubMed1995

Progressive scoliosis in Dubowitz syndrome.

STUDY DESIGN: This case report describes a 17-year-old male with Dubowitz syndrome in whom a progressive left thoracic scoliosis developed that required surgical correction. OBJECTIVE: Scoliosis associated with Dubowitz syndrome had not been previously described among the orthopedic manifestations of this rare syndrome. A review of the literature and the surgical treatment of this patient is presented. SUMMARY OF BACKGROUND DATA: Dubowitz syndrome is a rare autosomal recessive disorder characterized by microcephaly, craniofacial abnormalities, eczematous skin rash, delayed skeletal maturation, and shortness of stature. The orthopedic manifestations of this condition primarily involve the hands and feet with brachyclinodactyly of the fifth finger and syndactyly of the second and third toes. Spinal deformity in these individuals is not well described in the literature. METHODS: Over a 2-year period, the patient's scoliosis progressed to 88 degrees, resulting in severe truncal imbalance without neurologic sequelae. A posterior spinal fusion with segment instrumentation alone was used to correct the deformity. RESULTS: After surgery, excellent restoration of spine sagittal and coronal plane alignment was achieved, resulting in improved sitting and standing balance. CONCLUSION: Patients with Dubowitz syndrome may be at risk of having a progressive, rigid scoliosis. These individuals may need to be observed over a prolonged period for the development of spinal deformity because of the potential for extended delay in skeletal maturation.

Abnormalities, Multiple↗

PubMed1998

Goldberg-Shprintzen syndrome: report of a new family and review of the literature.

In 1981, Goldberg and Shprintzen described siblings with short-segment Hirschsprung disease, cleft palate, microcephaly, mild mental retardation, short stature and distinctive facial appearance. There have been several subsequent reports which broaden the phenotype. This paper describes a further family, reviews the literature and stresses the intra-familial variability.

Abnormalities, Multiple↗

PubMed1998

Cutis verticis gyrata-mental deficiency syndrome: report of a case with unusual neuroradiological findings.

The clinical and radiological features of a patient with Cutis Verticis Gyrata-Mental Deficiency syndrome are reported. The clinical features of the patient included severe mental retardation, drug resistant epilepsy, short stature, microcephaly with multiple furrows on the scalp and normally growing overlying hair. He was blind with bilateral optic atrophy, multiple joint contractures and spastic tetraplegia. Skull X-ray showed thickened calvarial bones but other features of pachydermoperiostosis were absent. Brain MRI showed well developed, albeit small, frontal and anterior temporal lobes with a normal gray-white matter interface. The parietal and occipital cortex were atrophic with widening of the occipital horns (colpocephaly). The sylvian fissures were accentuated because of atrophic parietal operculae. The splenium of the corpus callosum was hypoplastic. There was atrophy of the cerebellar cortex. Contrary to the previously described cerebral cortical polymicrogyria in Cutis Verticis Gyrata-Mental Deficiency syndrome, there was no evidence to suggest any migration disorder in our patient. The present report highlights the clinico-radiological heterogeneity of the syndrome.

Adult↗

PubMed2000

Raine dysplasia: a Brazilian case with a mild radiological involvement.

We report a preterm male infant, the first child of a young consanguineous couple, whose physical examination revealed craniofacial disproportion with microcephaly, wide fontanelles, exophthalmos, low nasal root and hypoplastic nose, long philtrum, small mouth, high arched and narrow palate, micrognathia, dysplastic, low-set and rounded ears, short neck and, arthrogryposis. Postmortem findings included hypoplastic lungs. Radiological examinations showed mild and localized increased of bone density in the cranial vault and skull base and facial bones and undermodelled in the long bones. The above findings are characteristics of Raine dysplasia but the case reported here presents a mild bone involvement with only a localized bone sclerosis and absence of prenatal fractures. We discuss the possibility that this case represents an allelic mutation of the Raine gene. The consanguinity of the parents reinforces the hypothesis of autosomal recessive inheritance for this entity.

Abnormalities, Multiple↗

PubMed2001

Humoral immunodeficiency with facial dysmorphology and limb anomalies: a new syndrome.

We report a 6 year old girl with an isolated humoral immune deficiency and a unique combination of dysmorphic features. Physical findings include microcephaly, micrognathia, sickle shaped eyebrows, hypoplastic alae nasi, thenar hypoplasia, partial 4-5 syndactyly of toes, recessed great toes, anterior anus, and hypoplastic labia minora. Radiographic findings include triphalangeal thumbs and hypoplastic first metatarsals. She has postnatal growth retardation and her development is substantially slower than her twin's. Her clinical course has been complicated by recurrent sinopulmonary infections and pneumococcal bacteraemia. Laboratory evaluation revealed hypogammaglobulinaemia, absent B cells, and a 46,XX karyotype. A review of the literature and the London Dysmorphology Database did not produce any recognizable syndromes that match her constellation of findings. She may represent a unique syndrome of unknown etiology.

Abnormalities, Multiple↗