Significance of genetic testing for paternal uniparental disomy of chromosome 6 in neonatal diabetes mellitus,☆☆

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Abstract

Two patients who presented at birth with neonatal diabetes mellitus (NDM) are described: one with paternal uniparental disomy for chromosome 6 and one with normal, biparental inheritance. The first child presented with low birth weight, macroglossia, hypertelorism, and club foot in addition to NDM. In this patient hyperglycemia was transient, and insulin treatment was discontinued at 4 months of age. The second child also presented with low birth weight but was normal in appearance, and insulin dependence continues after 5 years. Genetic analysis with polymorphic DNA markers for chromosome 6 indicated the presence of paternal uniparental disomy (UPD) in the first case and normal, biparental inheritance in the second case. Paternal UPD 6 has been reported in 8 previous cases of which 6 showed NDM. Three cases with paternal UPD 6 also included additional anomalies, such as macroglossia, not usually associated with NDM. Therefore the simultaneous finding of NDM and macroglossia should be a strong indicator for genetic testing. The genetic finding of paternal UPD 6 allows prediction of a transient, rather than permanent, form of diabetes mellitus and no increased recurrence risk of transient NDM in subsequent pregnancies. (J Pediatr 1999;134:42-6)

Section snippets

Patient 1

A male infant was born by cesarean section at 36 weeks’ gestation to a 39-year-old woman (gravida 4, para 3, abortion 1) of mixed European descent. The father was 5’9” tall and the mother 5’1”. The mother did not have gestational diabetes and had no family history of diabetes. Because of advanced maternal age, amniocentesis was performed and revealed a normal 46,XY male karyotype. Pregnancy was complicated by poor growth from 28 weeks and oligohydramnios. Apgar scores were 9 and 9 at 1 and 5

METHODS

For DNA polymorphism analysis, blood samples were obtained from each patient and both parents. Whole-cell lysates were prepared from peripheral blood by using the QIAamp blood lysis kit (Qiagen Inc, Santa Clarita, Calif). Microsatellite markers were selected based on their localization along chromosome 6, and primer pairs were acquired from Research Genetics (Huntsville, Ala).

The polymerase chain reactions were set up in a total volume of 10 μL. The reaction mixture contained 10 mmol/L Tris-HCl

RESULTS

The results of the DNA polymorphism analysis, with microsatellite markers extending along the length of chromosome 6, are presented in the Table for each patient and both parents. Patient 1 shows inheritance of a single paternal allele for 13 informative markers of 16 studied (Table, Fig 2).

. DNA polymorphism analysis of chromosome 6. Case 1 is presented in the left panel with the polymorphic marker D6S477. The father is heterozygous with alleles 1 and 2, and the mother is heterozygous with

DISCUSSION

NDM is a rare condition usually observed in conjunction with IUGR.10 In those cases with TNDM, only 18% of patients required insulin for more than 6 months, and the longest observed duration has been 18 months.11 Approximately one third to one half of the patients proved to have PNDM.1, 12, 13

Macroglossia in an infant with TNDM and IUGR was initially described by Dacou-Voutetakis et al14 in 1975. These authors identified 2 additional cases in the literature3, 15 and suggested that TNDM, IUGR,

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    Reprint requests: David H. Ledbetter, PhD, Department of Human Genetics, The University of Chicago, 924 East 57th St, Chicago, IL 60637.

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