Andrew Mueller, Skylar Muchmore, June-Anne Gold MD FACMG

Case history:

A genetic consult was requested for two 16-week-old dizygotic twins, one female and one male, born to G3P4 mother with advanced maternal age. At the time of the visit, the mother reported that she was concerned that both twins could have Prader-Willi Syndrome. Her doctor had told her this.

Baby Girl (BG) was born with respiratory distress at 31 3/7 weeks gestation. BW: 1435g BHC: 29cm BL: 35cm APGARS 1, 5: 4, 9.She was noted to have low tone and difficulty feeding following birth and was found to be plagiocephalic and brachiocephalic. Chromosome analysis studies found a translocation of chromosomes 15q and 21q. The chromosome microarray studies found 6.6 MB proximal deletion of 15q11.2q13.1 and 6.9 MB Proximal Duplication of 21q11.2q21.1, consistent with an unbalanced trans- location of 15q and 21q. The 21q micro duplication observed in BG does not overlap the Down syndrome critical region and is not currently associated with a clinical disorder. The 15q deletion includes the region associated with the Type I deletion of either Prader-Willi syndrome (PWS) or Angelman syndrome (AS), and the PWS / Angelman Methylation testing confirmed the absence of the paternal SNRPN gene expression confirming Prader-Willi Syndrome (PWS).

On physical exam, BG had features typical for PWS bi-temporal narrowing, almond-shaped eyes with upslanting palpebral fissures, downturned corners to the mouth, and severe hypotonia with decreased reflexes (Picture 1). She had hypoplastic labia andwas reportedly very still in pregnancy with decreased fetal movements. Growth percentiles were as follows: Length <1% (z=-3.59), weight <1% (-2.83), and head circumference <1% (z=-3.5). She had a nasogastric tube(NG) to help with nutrition, given feeding difficulties due to failure to thrive, severe hypotonia, and difficultysucking.

Her twin brother, Baby Boy (BB), was born at 31 3/7 weeks gestation with PTL and respiratory distress. BW: 1770g BHC: 30cm BL: 38cm APGARS 1, 5: 8, 9. His chromosomal microarray study found a 6.6MB terminal duplication of 15q11.2q13.1 and a 6.95MB terminal deletion of 21q11.2q21.1, consistent with an unbalanced translocation.

Compared to his twin, he was active during pregnancy, very fussy on examination, and had normal pigmentation. Growth percentiles at the time of the exam were: Length <1% (z=-3.13), weight 16% (z=-1.01), and head circumference 3% (z=-1.94) larger than his sister. He had different dysmorphic facial features with a broad nasal bridge, large low, set ears, deep nasolabial folds, wide open fontanelles, broad first toes, minimal 2-3 toe syndactyly, slightly increased tone, and deep palmar creases with short fingers and thumbs (Picture 2-3). During the examination, he was not fixing or following. His appearance and physical features are quite different from his sister’s.

The maternal family history was largely non-contributory. Mother had two healthy children from a previous relationship, and father has no other children. Parental consanguinity was denied. Maternal ancestry is from Guatemala, and paternal ancestry is from Honduras. One significant finding on the paternal side is that the paternal grandmother had three children who passed early in life. It is unclear why.

Assessment:

21q11.2q21.1 Duplication: Duplications of 21q have been associated with multiple phenotypic characteristics of Down syndrome when the Down Syndrome Critical Regions (DSCR) are duplicated (Olson et al.). In its most precise description, this region extends around 5.4 MB from between the D21S17 and D21S55 markers to MX1 and BCEI markers (Olson et al.). The 21q11.2q21.1 duplication found in BG notably does not include the DSCR. Duplications in these regions that do not include DSCR have been reported in individuals without a Down Syndrome phenotype or other mental and physical anomalies (Su et al.).

PWS can be confirmed with methylation studies, which test for the absence of paternal SNRPN gene expression. While PWS is generally the result of the de novo gene alterations mentioned above, here we see an instance consistent with a balanced translocation in the father.

PWS is uniquely characterized by a hypoactive fetus, leading to a hypotonic baby failing to thrive. Feeding habits drastically change between the ages of 2 and 4, and the child becomes hyperphagic. Severe morbid obesity is common without lifestyle intervention.

It is recommended that parents lock food away and take other precautions.

Like most syndromes, there is no definitive cure for PWS; however, a multidisciplinary approach involving lifestyle management, nutrition, genetics, physical, speech, and occupational therapy is recommended for favorable outcomes. Of note, growth hormone therapy managed with endocrinology has been found to increase lean muscle mass, decrease fat mass, and lead to a more favorable BMI (Driscoll et al.).

15q11.2q13.1 Duplication: The 15q11.2q13.1 duplication detected in BB is within an imprinting region of the genome. Due to this, the phenotype is dependent on the inheritance. Maternally inherited 15q duplications are associated with hypotonia, motor delay, intellectual disability, autism, and epilepsy (Lusk et al.). Paternally inherited 15q duplications usually have milder phenotypes and have been reported in individuals with developmental delay, speech delay, and autism (Ageeli et al.). The inheritance of the 15q duplication in BB is expected to be paternal, so his phenotype is expected to be milder.

21q11.2q21.1 Deletion: The 21q11.2q21.1 deletion observed in BB is associated with variable phenotypes, which include developmental delay, short stature, microcephaly, clinodactyly, low set ears, scoliosis, and cardiac anomalies, (Jespersgaard et al.). The 21q deletion could account for some of BB’s dysmorphic facial features. He is following up with cardiology for a hole in his heart that had reportedly closed.

Testing for the chromosome translocation was offered to the parents and declined at this time.

Take Away:

1. Carefully review genetic testing reports: The mother was under the impression that both of the children had Prader-Willi, which was reiterated during part of the appointment triage for the patients. A careful review of the genetic testing would have indicated two different diagnoses for the twins.
2. Balanced Translocations: Balanced translocations in a parent may result in 4 chromosome arrangements in their children. The two unbalanced translocations in the offspring may be associated with two differing phenotypes, as observed in the twins.

Citations:

1. Ageeli, Essam Al, Séverine Drunat, Catherine Delanoë, Laurence Perrin, Clarisse Baumann, Yline Capri, Jennifer Fabre-Teste, Azzedine Aboura, Céline Dupont, Stéphane Auvin, Laila El Khattabi, Dominique Chantereau, Anne Moncla, Anne-Claude Tabet, Alain Verloes, Duplication of the 15q11-q13 region: Clinical and genetic study of 30 new cases, European Journal of Medical Genetics, Volume 57, Issue 1, 2014, Pages 5-14,ISSN 1769-7212, https://doi.org/10.1016/j.ejmg.2013.10.008. (https://www.sciencedirect.com/science/article/pii/S1769721213002437)
2. Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. 1998 October 6 [Updated 2023 March 9]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993- 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1330/
3. Hiller B, Bradtke J, Balz H and Rieder H (2004): “CyDAS: a cytogenetic data analysis system,” BioInformatics 2005 21(7):1282-1283; doi:10.1093/bioinformatics/bti146. Bioinformatics Advance Access originally published online on November 16, 2004
4. Jespersgaard C, Damgaard IN, Cornelius N, Bache I, Knabe N, Miranda MJ, Tümer Z. Proximal 21q deletion as a result of a de novo unbalanced t(12;21) translocation in a patient with dysmorphic features, hepatomegaly, thick myocardium and delayed psychomotor development. Mol Cytogenet. 2016 February 4;9:11. doi:10.1186/s13039-016-0220-5. PMID: 26855673; PMCID: PMC4743331.
5. Lusk L, Vogel-Farley V, DiStefano C, Jeste S. Maternal 15q Duplication Syndrome. 2016 June 16 [updated 2021 July 15]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993– 2023. PMID: 27308687.
6. Olson LE, Richtsmeier JT, Leszl J, Reeves RH. A chromosome 21 critical region does not cause specific Down syn- drome phenotypes. Science. 2004 Oct 22;306(5696):687-90. doi:10.1126/science.1098992. PMID: 15499018; PMCID: PMC4019810.
7. Su, M.T.; Kuan, L.C.; Chou, Y.Y.; Tan, S.Y.; Kuo, T.C.; Kuo, P.L. Partial trisomy of chromosome 21 without the Down syndrome phenotype. Prenat. Diagn. 2016, 36, 492–495.

Disclosures: There are no reported disclosures