Index of suspicion.

Case 1: Facial and upper extremity weakness in a 16-year-old boy. Case 2: Hematochezia in a neonate. Case 3: bad body odor in a 13-year-old girl.

Duplication of the STS region in males is a benign copy-number variant.

Copy-number variants (CNVs) are a common finding in the human genome, with copy gains occurring at a higher frequency than losses in several databases of genomic variants in normal individuals. Copy gains of the steroid sulfatase (STS) gene have been seen in both males and females. Although deletion of STS in males is known to cause X-linked ichthyosis, the clinical significance of STS copy gains is less clear, with the duplication reported in individuals with abnormal phenotypes and normal relatives. We identified 72 males submitted to our laboratory for microarray-based comparative genomic hybridization with duplications in the STS region (chrX:6,465,812-8,093,195). In 40 (56%) patients, maternal blood was available, and the duplication was found to be inherited from the patient's apparently phenotypically normal mother in each of the 40 patients. We also identified three females who inherited a duplication of the STS region from phenotypically normal fathers, and a phenotypically normal uncle who had the same duplication as his nephews. In the remaining cases the inheritance could not be confirmed owing to lack of parental samples available for testing. Of the 72 subjects, 10 (14%) had an additional CNV elsewhere in the genome known to be clinically significant and likely causative of the patient's presenting symptoms. Based on the frequency with which duplications have been identified in clinically normal and abnormal individuals, we suggest a gain of STS in males is a population variant and unlikely to be clinically significant.

Microduplication of 4p16.3 due to an unbalanced translocation resulting in a mild phenotype.

With the widespread clinical use of comparative genomic hybridization chromosomal microarray technology, several previously unidentified clinically significant submicroscopic chromosome abnormalities have been discovered. Specifically, there have been reports of clinically significant microduplications found in regions of known microdeletion syndromes. In general, these microduplications have distinct features from those described in the corresponding microdeletion syndromes. We present a 5½-year-old patient with normal growth, borderline normal IQ, borderline hypertelorism, and speech and language delay who was found to have a submicroscopic 2.3 Mb terminal duplication involving the two proposed Wolf-Hirschhorn syndrome (WHS) critical regions at chromosome 4p16.3. This duplication was the result of a maternally inherited reciprocal translocation involving the breakpoints 4p16.3 and 17q25.3. Our patient's features are distinct from those described in WHS and are not as severe as those described in partial trisomy 4p. There are two other patients in the medical literature with 4p16.3 microduplications of similar size also involving the WHS critical regions. Our patient shows clinical overlap with these two patients, although overall her features are milder than what has been previously described. Our patient's features expand the knowledge of the clinical phenotype of a 4p16.3 microduplication and highlight the need for further information about it.

Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurobehavioral disorder manifested by infantile hypotonia and feeding difficulties in infancy, followed by morbid obesity secondary to hyperphagia. It is caused by deficiency of paternally expressed transcript(s) within the human chromosome region 15q11.2. PWS patients harboring balanced chromosomal translocations with breakpoints within small nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA) genes encoded downstream of SNRPN. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic, and molecular analyses including chromosome analysis, array comparative genomic hybridization (array CGH), expression studies, and single-nucleotide polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2 microdeletion on an 11-year-old child expressing the major components of the PWS phenotype. This child had an ∼236.29 kb microdeletion at 15q11.2 within the larger Prader-Willi/Angelman syndrome critical region that included the SNORD116 cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided evidence in support of the deletion being on the paternal chromosome 15. This child also met most of the major PWS diagnostic criteria including infantile hypotonia, early-onset morbid obesity, and hypogonadism. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype-phenotype correlations.

Molecular spectrum of SLC22A5 (OCTN2) gene mutations detected in 143 subjects evaluated for systemic carnitine deficiency.

Systemic primary carnitine deficiency (CDSP) is caused by recessive mutations in the SLC22A5 (OCTN2) gene encoding the plasmalemmal carnitine transporter and characterized by hypoketotic hypoglycemia, and skeletal and cardiac myopathy. The entire coding regions of the OCTN2 gene were sequenced in 143 unrelated subjects suspected of having CDSP. In 70 unrelated infants evaluated because of abnormal newborn screening (NBS) results, 48 were found to have at least 1 mutation/unclassified missense variant. Twenty-eight of 33 mothers whose infants had abnormal NBS results were found to carry at least 1 mutation/unclassified missense variant, including 11 asymptomatic mothers who had 2 mutations. Therefore, sequencing of the OCTN2 gene is recommended for infants with abnormal NBS results and for their mothers. Conversely, 52 unrelated subjects were tested due to clinical indications other than abnormal NBS and only 14 of them were found to have at least one mutation/unclassified variant. Custom designed oligonucleotide array CGH analysis revealed a heterozygous approximately 1.6 Mb deletion encompassing the entire OCTN2 gene in one subject who was apparently homozygous for the c.680G>A (p.R227H) mutation. Thus, copy number abnormalities at the OCTN2 locus should be considered if by sequencing, an apparently homozygous mutation or only one mutant allele is identified.

Hepatic failure, neonatal hemochromatosis and porto-pulmonary hypertension in a newborn with trisomy 21--a case report.

Liver failure in neonates is a rare but often fatal disease. Trisomy 21 is not usually associated with significant infantile liver disease. If present, hepatic dysfunction in an infant with Trisomy 21 is likely to be attributed to transient myeloproliferative disorder with hepatic infiltration by hematopoietic elements and may be associated with secondary hemosiderosis. A less commonly recognized cause of liver failure in neonates with Trisomy 21 is neonatal hemochromatosis (NH); this association has been reported in nine cases of Trisomy 21 in literature. NH is a rare, severe liver disease of intra-uterine onset that is characterized by neonatal liver failure and hepatic and extrahepatic iron accumulation that spares the reticuloendothelial system. NH is the most frequently recognized cause of liver failure in neonates and the commonest indication for neonatal liver transplantation. Although porto-pulmonary hypertension (PPH) has been reported as a complication of liver failure in adults and older children, this has not been reported in neonates with liver failure of any etiology. This is probably due to the rarity of liver failure in newborns, delayed diagnosis and high mortality. The importance of recognizing PPH is that it is reversible with liver transplantation but at the same time increases the risk of post-operative mortality. Therefore, early diagnosis of PPH is critical so that early intervention can improve the chances of successful liver transplantation. We report for the first time the association of liver failure with porto-pulmonary hypertension secondary to NH in an infant with Trisomy 21.

Maternal systemic primary carnitine deficiency uncovered by newborn screening: clinical, biochemical, and molecular aspects.

BACKGROUND: Systemic primary carnitine deficiency is an autosomal recessive disorder of the carnitine cycle caused by mutations in the SLC22A5 gene that encodes the carnitine transporter, organic cation transporter. Systemic primary carnitine deficiency typically presents in childhood with either metabolic decompensation or cardiomyopathy. We report five families in which low free carnitine levels in the infants' newborn screening have led to the diagnosis of maternal systemic primary carnitine deficiency. METHODS: Blood samples from the infants and /or their family members were used to extract the DNA. The entire coding regions of the SLC22A5 gene were sequenced. The clinical data were obtained from the referring metabolic specialists. RESULT: Sequencing the SLC22A5 gene allowed molecular confirmation with identification of three novel mutations: c.1195C>T (p.R399W), c.1324_1325GC>AT (p.A442I), and c.43G>T (p.G15W). All infants were asymptomatic at the time of diagnosis, and one was found to have systemic primary carnitine deficiency. Three mothers are asymptomatic, one had decreased stamina during pregnancy, and one has mild fatigability and developed preeclampsia. DISCUSSION: These findings provide further evidence that systemic primary carnitine deficiency presents with a broad clinical spectrum from a metabolic decompensation in infancy to an asymptomatic adult. The maternal systemic primary carnitine deficiency was uncovered by the newborn screening results supporting the previous notion that newborn screening can identify some of the maternal inborn errors of metabolism. It also emphasizes the importance of maternal evaluation after identification of a low free carnitine level in the newborn screening.

Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency.

BACKGROUND: Nuclear factor kappaB (NF-kappaB) is a master transcriptional regulator critical for ectodermal development and normal innate and adaptive immune function. Mutations in the IkappaB kinase gamma/NF-kappaB essential modifier have been described in male subjects with the syndrome of X-linked ectodermal dysplasia with immune deficiency that results from impaired activation of NF-kappaB. OBJECTIVES: We sought to determine the genetic cause of ectodermal dysplasia with immune deficiency in a female patient. METHODS: Toll-like receptor-induced production of the NF-kappaB-dependent cytokines TNF-alpha and IFN-alpha was examined by means of ELISA, the patient's IkappaBalpha gene was sequenced, and NF-kappaB activation was evaluated by means of electrophoretic mobility shift assay and NF-kappaB-luciferase assays in transfectants. RESULTS: Toll-like receptor function was impaired in the patient. Sequencing of the patient's IkappaBalpha gene revealed a novel heterozygous mutation at amino acid 11 (W11X). The mutant IkappaBalphaW11X protein did not undergo ligand-induced phosphorylation or degradation and retained NF-kappaB in the cytoplasm. This led to roughly a 50% decrease in NF-kappaB DNA-binding activity, leading to functional haploinsufficiency of NF-kappaB activation. Unlike the only other reported IkappaBalpha mutant associated with ectodermal dysplasia associated with immune deficiency (ED-ID), S32I, IkappaBalphaW11X exerted no dominant-negative effect. CONCLUSIONS: Functional NF-kappaB haploinsufficiency was associated with ED-ID, and this strongly suggests that normal ectodermal development and immune function are stringently dependent on NF-kappaB in that they might require more than half of normal NF-kappaB activity. CLINICAL IMPLICATIONS: Although ED-ID is well described in male subjects, female subjects can present with a similar syndrome of ectodermal dysplasia with immune deficiency resulting from mutations in autosomal genes within the NF-kappaB pathway.

Growth spurt hypocalcemia.

This is a clinical presentation of a healthy 12-year-old African-American male who had symptomatic hypocalcemia during a growth spurt that resolved after reaching a stable height. He had clinical findings consistent with Pseudohypoparathyroidism (PHP) with hypocalcemia, hyperphospatemia, and increased parathyroid hormone (PTH) concentration. We hypothesize that his family might have a hitherto unreported autosomal dominant PHP-Ib that may or may not be linked to the GNAS locus.

The neuropsychological phenotype of velocardiofacial syndrome (VCFS): relationship to psychopathology.

Children with velocardiofacial syndrome (VCFS; N=14) and a comparison group of siblings (N=8) underwent comprehensive neuropsychological assessment to examine the relationship between cognitive functioning and psychopathology. Significant group differences were obtained on tests of full scale and verbal intellectual functioning and perceptual-motor skills. With the exception of performance on tests of attention and executive functioning, children with VCFS displayed a profile consistent with nonverbal learning disability (NLD). However, within group comparisons revealed significantly poorer visuospatial intellectual and nonverbal memory functioning in sibling controls as well. No significant group differences were obtained on tests of motor speed, academic, language, attention, memory, or executive functioning, with significant variability in children with VCFS frequently accounting for the lack of robust differences. Parent-report measures revealed profiles consistent with ADHD. No clinically significant symptoms of psychosis, depression or anxiety were noted on either self- or parent-report measures. Wisconsin Card Sorting Test performance was found to be highly and negatively correlated with the Thought Problems subscale of the Child Behavior Checklist (CBCL) for VCFS children only, suggesting a possible at-risk indicator for later onset psychopathology.

A syndrome of hypoplastic sinuses, hydrocephalus, bronchiectasis, and hypogammaglobulinemia with functional antibody deficiency in twin girls.

BACKGROUND: A variety of syndromes are known to be associated with immune deficiency, some as a major part of the syndrome and some as an occasional finding. OBJECTIVES: To report a newly defined syndrome of hydrocephalus, hypoplastic sinuses, cartilaginous webbing of the bronchi, bronchiectasis, and hypogammaglobulinemia with functional antibody deficiency in identical twin girls. METHODS: Spirometry, radiography, computed tomography (CT), bronchoscopy, and laboratory tests were performed for diagnosis. RESULTS: A girl (twin A) was evaluated at the age of 7 years for chronic cough and wheeze that worsened with exercise. Hydrocephalus had been diagnosed a year before evaluation. She was treated for cough variant asthma and was lost to follow-up until the age of 10 years. The cough had worsened progressively, and dyspnea was now apparent. Spirometry was consistent with reversible airway obstruction. A chest radiograph was suggestive of bronchiectasis. A chest CT scan showed bilateral upper lobe bronchiectasis. Hypogammaglobulinemia and functional antibody deficiency were noted. A CT scan of the sinuses revealed aplasia or severe hypoplasia of all the paranasal sinuses. Bronchoscopy revealed a grossly abnormal bronchial structure and atrophic-appearing bronchial mucosa. Twin B also had a history of hydrocephalus. Although she had no respiratory symptoms, chest CT revealed bronchiectasis, and she had obstruction on spirometry. Laboratory analysis revealed hypogammaglobulinemia and functional antibody deficiency. She became symptomatic 2 years after twin A. CONCLUSIONS: This is a newly reported syndrome of hydrocephalus, absent sinuses, abnormalities of the bronchi, and functional antibody deficiency, which initially presented as cough and wheeze.

Memory and learning in children with 22q11.2 deletion syndrome: evidence for ventral and dorsal stream disruption?

This study examined memory functioning in children and adolescents with 22q11.2 Deletion Syndrome (DS; velocardiofacial syndrome). An overall verbal better than nonverbal memory pattern was evident on the Test of Memory and Learning (TOMAL), with children with 22q11.2 DS performing significantly below their siblings and children with low average IQ but similar to children with autism on facial memory. Children with 22q11 DS also performed significantly below their siblings on tests of verbal working memory. Children with autism performed significantly poorer than the siblings of children with 22q11.2 DS only on their recall of stories. Delayed recall was significantly poorer in children with 22q11.2 DS and children with autism, compared to sibling controls. Although there were no significant group differences on tests of multiple trial verbal or visual learning, a relative weakness was noted with multiple trial visual learning in children with 22q11.2 DS and their siblings, suggesting that an alternative or interactive factor other than the deletion may account for the relatively better verbal compared to nonverbal memory abilities. Deficits in facial memory in children with both 22q11.2 DS and autism suggest disruptions in ventral temporal pathways such as between fusiform gyrus and parahippocampal/hippocampal regions whereas deficits in verbal working memory in children with 22q11.2 DS implicates dorsolateral prefrontal regions, both intimating aberrant white matter pathways.

Transmission of ring chromosome 13 from a mother to daughter with both having a 46,XX, r(13)(p13q34) karyotype.

Ring chromosomes are thought to be the result of breakage in both arms of a chromosome, with fusion of the points of fracture and loss of the distal fragments. Another mechanism of ring formation is believed to be the simple fusion of chromosome ends with preservation of telomeric and subtelomeric sequences. Ring chromosome 13 was first described in 1968 and its incidence estimated at 1 in 58,000 live births. Severe phenotypes associated with large deletions of 13q have been described as "ring chromosome 13 syndrome." Features of the "ring chromosome 13 syndrome" include mental retardation (often severe), growth retardation, microcephaly, facial dysmorphism, and hand, foot or toe abnormalities. We report on a case of a mother and daughter with r(13) and mild phenotypes. Our patient, IA, had chromosome analysis performed at about 4(1/2) years of age due to some developmental delay. This revealed 46,XX, r(13)(p13q34) karyotype with no loss of any chromosomal band. Her mother, EA, was subsequently found to have the same ring 13. IA's maternal grandmother had a normal karyotype while her maternal grandfather was unavailable for testing. Fluorescence in situ hybridization (FISH) analysis showed loss of a specific subtelomeric 13q region in r(13) in the mother. Clinically, IA had macular hyperpigmentation on the chin and mild delay in speech and fine motor skills. EA, 22 years of age, had mild short stature and borderline mental retardation. To our knowledge, this is the first report of a case of familial transmission of r(13). We compare phenotypes of our cases with those from other reported cases of r(13) and discuss the possible mechanism of formation of this ring chromosome.

Medulloblastoma with adverse reaction to radiation therapy in nijmegen breakage syndrome.

A 3-year-old child with microcephaly, facial dysmorphism, growth retardation, and developmental delay was diagnosed with medulloblastoma. Craniospinal irradiation resulted in severe radiation-induced dermatitis and gastroesophagitis, unresponsive to further medical therapy. Colony survival assay on the patient's transformed lymphocytes revealed a high degree of radiosensitivity ex vivo. The presence of radiation sensitivity, both clinically and ex vivo, in association with microcephaly and growth retardation, prompted a diagnostic workup for Nijmegen breakage syndrome. The patient was confirmed to have a compound heterozygote genotype for the common founder mutation of NBS1 675del5 in exon 6, and 1142delC in exon 10. Because irradiation is an important component of therapy for brain tumors, caution should be exercised in cancer patients with associated microcephaly and growth retardation, as they may turn out to have the rare diagnosis of Nijmegen breakage syndrome.

Evaluation of surgical intervention in familial isolated simple ectopia lentis: younger v. older generations.

BACKGROUND: There continues to be a debate whether surgical management of ectopia lentis in children is an appropriate course to improve visual acuity and prevent further amblyopia over medical and optical management. The long term outcome and postoperative status of three generations of patients in a single family with simple ectopia lentis is presented. SUBJECTS: Nine family members (ages 6-61 years) were evaluated at Children's Hospital of Michigan (CHM) (6 patients) and Kresge Eye Institute (KEI) (3 patients) for primary or secondary visual acuity problems and a family history of simple bilateral ectopia lentis without any systemic manifestations. RESULTS: Three of the four children with ectopia lentis had improved postoperative vision OU and one child was moderately amblyopic following lensectomy with 6 years followup. Of the older generation, one of the three adults had removal of dislocated lenses, with 20/50 amblyopia in one eye and 20/25 vision in the other. The other two adults were treated for end stage glaucoma with poor visual acuity. CONCLUSIONS: For the younger generations of this family, surgical intervention for simple ectopia lentis provided improvement in visual acuity. Without surgery, amblyopia may have occurred in one or both eyes. For the oldest generation of this family, glaucoma and poor vision was the end result. Hopefully, the earlier treatment of the ectopia lentis in these children will result in better vision now and in the long term.