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Intrinsic factor deficiency (OMIM #261000, IFD) is a rare inherited disorder of vitamin B12 metabolism due to mutations in the gastric intrinsic factor (GIF) gene. We report three individuals from an Old Order Mennonite community who presented with B12 deficiency. Two cases are siblings born to consanguineous parents and the third case is not known to be closely related. The older male sib presented at 4 years with gastrointestinal symptoms, listlessness, and pallor. He had pancytopenia with megaloblastic anemia. Serum B12 was 61 (198–615 pmol/L). Methylmalonic aciduria was present. C3 was elevated on acylcarnitine profile. Homocysteine was high at 16.7 (5.0–12.0 umol/L). His asymptomatic female sibling was also found to have B12 deficiency. Genetic testing for methylmalonic aciduria (MMAA), transcobalamin deficiency (TCN2), and Imerslund-Gräsbeck syndrome (AMN) showed no mutation in both siblings. The third patient, a 34-year-old woman, had presented in infancy with a diagnosis of pernicious anemia. Mutation analysis of GIF revealed compound heterozygosity for a c.79+1G>A substitution and a c.973delG deletion in all three individuals. Oral or parenteral vitamin B12 has led to complete recovery of clinical parameters and vitamin B12 levels. Newborn screening samples on the siblings revealed normal methylcitrate, C3, and C3/C2 ratios thus indicating no disruption of propionic or methylmalonic acid metabolism. A high index of suspicion should be maintained if children present with megaloblastic anemia since GIF deficiency is a treatable disorder and newborn screening may not be able to detect this condition.

OBJECTIVES: (1) To present a case with prenatally detected idic Yp. (2) To review literature to assess if there is a correlation between the proportion of amniocytes with idic Yp and phenotypic sex. METHODS: Seventeen cases were reviewed. RESULTS: Amniocentesis was done due to positive integrated prenatal screening result. Interphase FISH was normal for chromosomes 13, 18, and 21, but mosaic for cell lines with 1 X and 0 to 2 copies of DYZ3, SRY, or DYZ1(Yq12). Amniocytes had 45,X[28]/46,X,idic(Y)(q11.2)[2].ish idic(Y)(DYZ3 + +, SRY + +). An apparently normal female was born at 37 weeks. The umbilical cord had 45,X[50], but cord blood had 45,X[17]/46,X,idic(Y)[31]/47,X,idic(Y)x2[2]. Review of 17 cases showed that 13 cases with 20 to 100% cells with idic Yp all had a male phenotype. Two cases with 3 and 7% of idic Yp cells had a female phenotype. Two cases with 45,X only at prenatal diagnosis but idic Yp detected postnatally were phenotypic male. CONCLUSION: (1) We present the first report of prenatally detected idic Yp and Yq12 resulting in an apparently normal female at birth. (2) Finding of > 20% of G-banded amniocytes with idic Yp in the absence of other indicators of foetal structural anomalies seems to correlate with phenotypically normal male in most cases.

Mutations in the cohesin regulators NIPBL and ESCO2 are causative of the Cornelia de Lange syndrome (CdLS) and Roberts or SC phocomelia syndrome, respectively. Recently, mutations in the cohesin complex structural component SMC1A have been identified in two probands with features of CdLS. Here, we report the identification of a mutation in the gene encoding the complementary subunit of the cohesin heterodimer, SMC3, and 14 additional SMC1A mutations. All mutations are predicted to retain an open reading frame, and no truncating mutations were identified. Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics. Our data indicate that SMC3 and SMC1A mutations (1) contribute to approximately 5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation.