Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions.

TBR1 encodes a transcription factor with critical roles in corticogenesis, including cortical neuron migration and axon pathfinding, establishment of regional and laminar identity of cortical neurons, and control of glutamatergic neuronal cell fate. Based upon TBR1's role in cortical development, we sought to investigate TBR1 hemizygosity in individuals referred for genetic evaluation of intellectual disability and developmental delay. We describe 4 patients with microdeletions identified by molecular cytogenetic techniques, encompassing TBR1 and spanning 2q24.1q31.1, ranging in size from 2.17 to 12.34 Mb. Only the patient with the largest deletion had a possible cortical malformation. Mild ventriculomegaly is the only common brain anomaly, present in all patients; a Chiari I malformation is seen in 2 patients, and mega cisterna magna is seen in a third. Our findings are consistent with Tbr1 mouse models showing that hemizygosity of the gene requires additional genetic factors for the manifestation of severe structural brain malformations. Other syndromic features are present in these patients, including autism spectrum disorders, ocular colobomas, and craniosynostosis, features that are likely affected by the deletion of genes other than TBR1.

D-2-Hydroxyglutaric aciduria with absence of corpus callosum and neonatal intracranial haemorrhage.

We report D-2-hydroxyglutaric aciduria in a neonate with intracranial haemorrhage and absence of the corpus callosum. D-2-hydroxyglutaric acid was confirmed by specific chiral derivatization gas chromatography-mass spectrometry. Absence of the corpus callosum and spontaneous neonatal intracranial haemorrhage should raise the suspicion for metabolic disease, and especially organic acidurias.

Deletion of 2q37 and duplication of 10q24: two cases in the same family and review of the literature.

We describe two patients (first cousins, once removed) with an unusual head shape, high arched palate, flat nasal bridge, abnormal ears, hand and feet abnormalities and other anomalies. The patients were ascertained independently and it was initially unknown that they were related to each other. Cytogenetic and fluorescent in situ hybridization (FISH) analysis identified a der(2)t(2;10)(q37.3;q24.1) unbalanced translocation resulting in loss of 2q37.3-qter and duplication 10q24.1-qter. The clinical features of these two patients are compared with previously described cases of 2q deletion and 10q duplication. These patients also emphasize the difficulty in some families of understanding and sharing genetic information and in the difficulties in obtaining an accurate pedigree in a genetics clinic.

Arginine deficiency-induced hyperammonemia in a home total parenteral nutrition-dependent patient: a case report.

BACKGROUND: Patients with short bowel syndrome and renal dysfunction with TPN dependence are at high risk for developing hyperammonemia if the TPN does not contain sufficient quantities of arginine. Providing proper nutrition support is essential in the management of these patients. METHODS: We report on a patient with short bowel syndrome, TPN dependence, and normal renal function who developed hyperammonemic encephalopathy due to inadvertent lack of arginine in his TPN. RESULTS: The patient was successfully treated with hemodialysis and an IV arginine infusion to resolve the hyperammonemia. His home TPN was also adjusted such that arginine was added to his subsequent solutions. CONCLUSIONS: Our patient underscores the importance of adequate and sustained arginine supplementation to avoid hyperammonemia in TPN dependent patients with short bowel syndrome.

Analphoid 3qter markers.

Two cases of marker chromosomes derived from a non-centromeric location were studied to determine the characteristics of these markers with respect to the presence of functional centromeres and whether an associated phenotype could be described. The markers were characterized by fluorescence in situ hybridization and centromeric protein studies. Assessments were done to identify clinical features. Case 1 is a girl referred at age 1.5 years with swirly areas of hyperpigmentation, bilateral preauricular pits, hypotonia, developmental delay, and seizures. Case 2 is a male first evaluated as a newborn and then later during the first year of life. He had streaky hypopigmentation, right preauricular pit, accessory nipples, postaxial polydactyly, asymmetric cerebral ventricles, duplicated right kidney, a right pulmonary artery stenosis, and seizures. Mosaicism for an extra marker from the 3qter region was present in both cases. Both markers had a constriction near one end and were C-band negative. Centromeric protein studies indicated absence of CENP-B, presence of CENP-C (data for case 1 only), and presence of CENP-E. Marker chromosomes were thus identified with a chromosomal origin far from their usual centromeric region and yet appeared to have functional centromeres. These two cases did not permit a specific clinical phenotype to be ascribed to the presence of tetrasomy for 3q26.2 approximately 3q27.2-->3qter.

Blau syndrome (familial granulomatous arthritis, iritis, and rash) in an african-american family.

Blau syndrome (familial granulomatous arthritis, iritis, and rash) was originally described in 1985, in 11 members of a family of Dutch ancestry. Inheritance is autosomal dominant. Several more Caucasian families have been described since. Skin and synovial biopsy specimens show noncaseating sarcoid like granulomas, but the lung is not involved as in classic sarcoidosis. This report describes 3 members of an African American family with Blau syndrome. It is important to differentiate this genetic disorder from other childhood arthritides, such as, juvenile rheumatoid arthritis, juvenile spondyloarthropathies, and early-onset sarcoidosis, because of the need for genetic counseling, treatment and differing potential for selective involvement of other organs (eye, skin, and tendons/joints). All children of an affected individual have a 50% chance of inheriting the disease. Unaffected children do not have to be concerned about subsequent generations being affected. The response to conventional treatments used in juvenile rheumatoid arthritis and to etanercept in our patients has not been satisfactory. Joint disease responds to corticosteroids, but these agents are not suitable for a disease that is lifelong. The eye involvement is aggressive and can lead to blindness. These patients need close follow-up by an ophthalmologist.

Adult and two children with fetal methotrexate syndrome.

The folic acid antagonists, methotrexate and aminopterin, are known to be teratogenic in humans. The critical period for their teratogenecity is suspected to be between 6 to 8 weeks post-conception. Fetal exposure from 10 to 32 weeks weeks post-conception to methotrexate alone or in combination with other anti-cancer drugs has not resulted in obvious teratogenic effects. Methotrexate is often used to treat cancers but is occasionally used as an abortifacient. The long-term outcome of the fetal aminopterin syndrome has been published in only four adults. We report on a 28-year-old man with fetal methotrexate syndrome and two children with mild manifestations of the syndrome. One child was inadvertently exposed to methotrexate from 7 1/2 through 30 weeks post-conception because his mother was receiving it for treatment of breast cancer. The other was exposed from 11 weeks and 5 days through 25 weeks in an attempt to induce abortion. The 28-year-old man has craniofacial and digital anomalies, growth retardation but normal intelligence as noted in the previously reported cases. These cases remind us of the teratogenicity of methotrexate and should serve as a warning that if methotrexate is used as an abortifaciant and an abortion does not ensue, there is a teratogenic risk.

Hearing, language, speech, vestibular, and dentofacial disorders in fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) is characterized by congenital anomalies traditionally associated with hearing disorders. The present study sought to (a) evaluate possible central hearing loss; (b) verify and extend previous observations on sensorineural and conductive hearing losses; (c) evaluate possible vestibular disorders; (d) examine the relationships between hearing, speech, language, vestibular, and dentofacial disorders in FAS patients; and (e) evaluate the influence of patient age, race, and gender on the expression of these morbidities. A biracial group of 22 FAS patients (aged 3 to 26 years) were evaluated by standard hearing, speech, language, and vestibular tests. Dentofacial and other malformations were also assessed. Of the 22 FAS patients, 17 (77%) had intermittent conductive hearing loss due to recurrent serous otitis media that persisted from early childhood into adulthood, whereas 6 (27%) had sensorineural hearing loss in addition to the conductive hearing loss. Among the 12 patients tested for central hearing function, all (100%) were significantly impaired. Among the patients tested for speech and language ability, 18 of 20 (90%) had speech pathology, 16 of 21 (76%) had expressive language deficits, and 18 of 22 (82%) had receptive language deficits. Hearing, speech, and language deficits were not influenced by age, race, or gender. On the vestibular tests, all performed within normal limits with the possible exception of one child (n = 6). High incidences of dentofacial, temporomandibular joint, ocular, cardiac, and skeletal disorders were observed. Race and gender tended to influence dental malocclusion class. Two subjects exhibited autistic tendencies. In conclusion, new and important findings included a high prevalence of sensorineural, conductive, and central hearing deficits, the persistence of otitis proneness into adulthood, the existence of temporomandibular joint disorders, and the possible influence of gender or race on dental malocclusions. Such disorders can contribute to the learning, behavioral, and emotional difficulties seen in FAS patients and warrant early, aggressive intervention.

The genetic implication for preceding generations of the prenatal diagnosis of interrupted aortic arch in association with unsuspected DiGeorge anomaly.

We present a case of prenatally diagnosed interrupted aortic arch with a ventricular septal defect in the presence of maternal congenital heart disease, which led to the detection of segmental monosomy of chromosome 22q11.2 in both patients. The implications of detecting a microdeletion and the importance of a multidisciplinary approach to prenatal diagnosis and counseling are discussed.

Familial infantile olivopontocerebellar atrophy.

Infantile olivopontocerebellar atrophies are rare progressive, fatal, neurologic conditions characterized pathologically by loss of neurons and gliosis in the cerebellum, pons, and inferior olivary nuclei in early life. The clinical and pathologic features of 2 brothers who presented in early infancy with failure to thrive and neurologic deterioration leading to death by the age of 5 months are reported. Magnetic resonance imaging of the brain of Patient 1 disclosed progressive pontocerebellar atrophy. Both siblings had identical patterns of neuronal loss consistent with olivopontocerebellar atrophy at postmortem examination. Serum biochemical abnormalities of low thyroid binding globulin, hypoalbuminemia, and low cholesterol, suggestive of the carbohydrate-deficient glycoprotein syndrome, were also present in both patients.

Spontaneous contraction of leukodermic patches in Waardenburg syndrome.

Waardenburg Syndrome is an autosomal dominantly inherited disorder with variable penetrance. It is a rare disorder with an estimated frequency of 1:20,000 in Kenya (East Africa) and 1:40,000, in the Netherlands presenting with or without deafness. The frequency with deafness is lower, estimated at 1:50,000 to 1:212,000. The major characteristic features are as follows, with reported incidences in parenthesis: 1) Dystopia canthorum (99%); 2) synophrys (17%-69%); 3) broad nasal root (78%); 4) depigmentation of hair, skin, or both (17%-58% with white forelock); 5) heterochromic or hypochromic irides (greater than 20%); 6) congenital deafness (9%-38%). Genetic heterogeneity has led to classification of affected families as type I, with dystopia canthorum, or type II, without dystopia canthorum (2, 6). Piebaldism and Woolf's Syndrome can present with pigmentary changes which are similar to Waardenburg Syndrome. Woolf's Syndrome also includes deafness. However, the distinguishing structural ophthomologic abnormalities of dystopia canthorum, broad nasal root, and synophrys are not found in either piebaldism or Woolf's Syndrome. The congenital patterns of leukoderma in both piebaldism and Waardenburg Syndrome has been believed to be stable throughout the lifetime of the affected individuals. We report an otherwise typical family with Waardenburg Syndrome, type I, in which 2 members atypically demonstrate spontaneous pigmentation and contraction of congenital leukodermic patches. To our knowledge, this has not been previously reported in Waardenburg Syndrome.

Molecular abnormalities of a phosphoglycerate kinase variant generated by spontaneous mutation.

A new case of X chromosome-linked phosphoglycerate kinase (PGK) abnormality is described. The male proband was mentally retarded, had behavior disorders, and displayed episodes of hemolytic anemia. The enzyme activity of red blood cells from the patient was about 10% of normal, and that of the cultured fibroblasts was about 50% of normal cells. The variant PGK was characterized by a lower affinity for the substrates, reduced thermostability, and increased anodal electrophoretic mobility. The pH activity profile of the variant enzyme was different from that of normal. The amount of messenger RNA (mRNA) in the variant fibroblasts was comparable to that of normal fibroblasts. The mRNA coding for PGK was subjected to coupled reverse transcription followed by amplification by the polymerase chain reaction. Nucleotide sequence of the variant cDNA showed a point mutation, T/A----C/G transition, in exon 9 of the variant gene. No other mutation was found in all coding regions of the variant. The mutation should cause Cys----Arg substitution at the 315th position from the NH2-terminal Ser of PGK, and it created an additional Ava II (or isoschimatic) cleavage site in the variant gene. Because the variant gene was not detected in the proband's mother and siblings, it must have been generated by spontaneous mutation during oogenesis.

Nonimmune hydrops fetalis in Noonan's syndrome.

Nonimmune hydrops fetalis has been reported to be associated with congenital malformations. We describe two newborns with Noonan's syndrome who presented with nonimmune hydrops fetalis that was most likely secondary to a generalized lymphatic vessel dysplasia. Other manifestations of lymphatic abnormalities in Noonan's syndrome, such as pedal edema and pulmonary and intestinal lymphangiectasis, have been observed in children. Nonimmune hydrops represents one end of the spectrum of abnormalities seen in this syndrome.