NeoQuest November 2024: Diagnostic Testing for Neonate with Multiple Congenital Anomalies

A prenatal visit revealed a fetus with polyhydramnios, limb anomalies, and a significant congenital anomaly (Figure 1A). Results from cell-free DNA screening revealed a male fetus with low risk for Trisomy 21, 18, and 13. At birth, the infant required emergent intubation. A postnatal radiograph confirmed limb anomalies seen on prenatal ultrasound (Figure 1B). 

Figure 1. A. Fetal MRI and B. Lower extremity radiograph. Image from: Chitkara R, Chock V, Barth R, Dahmoush H, Smith C, Matalon DR, Herring M, Susan Hintz S, Pallister-Killian Syndrome. Neoreviews. 2024;25(11):e751–e756.¹

In addition to a serum microarray, which of the following tests would help confirm this infant’s diagnosis?

1. Bone marrow analysis
2. Distal upper extremity radiograph
3. Pelvic ultrasonography
4. Skin fibroblast analysis

Answer: D. Skin fibroblast analysis

Explanation:

The fetal MRI shows the presence of a left congenital diaphragmatic hernia (CDH) (black arrows), which is displacing the heart (white arrow) into the right chest (Figure 1A).¹ The radiograph of the lower extremities is notable for bilateral rhizomelic limb shortening (Figure 1B).¹ Polyhydramnios, congenital diaphragmatic hernia, and rhizomelia are the three most common prenatal ultrasound findings in Pallister-Killian syndrome (PKS).²  

PKS is a rare multi-organ genetic disease caused by tissue-limited tetrasomy 12p mosaicism.³ Characteristic facial features include frontoparietal alopecia, frontal bossing, and extension of the philtrum into the upper vermillion border.³ Other commonly affected organs include the brain (structural brain anomalies associated with seizures), heart (bicuspid aortic valve, patent ductus arteriosus), respiratory/gastrointestinal (congenital diaphragmatic hernia), musculoskeletal system (polydactyly and rhizomelia), and skin (variations in pigmentation from mosaicism) (Figure 2).³ Due to the presence of tissue-limited mosaicism and the rapid replacement of lymphocytes, serum chromosomal microarray analysis (CMA) alone is suboptimal in identifying patients with PKS.⁴ Tissue fibroblasts, amniotic, and chorionic villi cells all possess a greater degree of mosaicism compared to serum cell lines and are more likely to yield a diagnosis of PKS (Option D).⁵

Figure 2: Variations in skin pigmentation due to mosaicism similar to what would be seen in patients with Pallister-Killian syndrome. From: Habeshian KA, Kirkorian AY. Congenital Pigmentary Anomalies in the Newborn. Neoreviews. 2021;22(10):e660–e672.  

Diamond-Blackfan anemia (DBA) is a congenital red blood cell disorder characterized by a pure red cell aplasia.⁶ Patients with DBA frequently present with craniofacial abnormalities (cleft lip and palate), thumb anomalies (triphalangeal thumb), and congenital cardiac disease (ventricular septal defect, atrial septal defect).⁶ The diagnosis of DBA can be made with bone marrow analysis (Option A), which will show normal myeloid and megakaryocyte cell lines. DBA is not typically associated with polyhydramnios, CDH, or rhizomelia.

Fryns syndrome is another rare multiorgan genetic disease associated with CDH and other diaphragmatic defects (including eventration, hypoplasia, and agenesis).^7,8 In addition to diaphragmatic defects, other hallmark characteristics of Fryns syndrome include characteristic facial features (coarse face, wide-set eyes, wide and depressed nasal bridge), short distal phalanges of the fingers and toes (Option B), significant pulmonary hypoplasia, and a family history consistent with an autosomal recessive mode of inheritance.⁸ Fryns syndrome can be clinically diagnosed based on established clinical diagnostic criteria or with molecular genetic testing showing biallelic pathogenic variants in PIGN.⁸ Unlike PKS, rhizomelia is not typically seen in Fryns syndrome.

Pelvic ultrasonography (Option C) could aid in the diagnosis of Denys-Drash syndrome, particularly for 46,XY patients with ambiguous genitalia.⁹ Denys-Drash syndrome is caused by an autosomal dominant WT1 (Wilms tumor gene 1) mutation.⁹ The classic triad of Denys-Drash syndrome is congenital nephrotic syndrome leading to end-stage renal disease, ambiguous genitalia in XY individuals (normal genitalia in 46,XX individuals), and Wilms tumor. ⁹ Though rare, CDH has been reported to occur in patients with Denys-Drash syndrome.¹⁰ Denys-Drash is not typically associated with limb anomalies or polyhydramnios.⁹  

Did you know?
All known cases of PKS have been due to sporadic mutations. The recurrence risk of PKS is thus equivalent to the incidence of PKS in the general population (approximately 1/20,000 liveborn infants).²

What are the most common syndromic and non-syndromic anomalies associated with CDH? To find the answer, please refer to the following article: Kays DW, Congenital diaphragmatic hernia: real improvements in survival. Neoreviews. 2006;7(8):e428–e439

NeoQuest November 2024 Authors:
Angelina June MD, FAAP, Fairfax Neonatal Associates, Fairfax, Virginia
Neena Jube-Desai, MD, MBA, FAAP, Children’s National Hospital/George Washington University Hospital, Washington, DC

References

1. Chitkara R, Chock V, Barth R, Dahmoush H, Smith C, Matalon DR, Herring M, Susan Hintz S, Pallister-Killian syndrome. Neoreviews. 2024;25(11):e751–e756
2. Doray B, Girard-Lemaire F, Gasser B, et al. Pallister-Killian syndrome: difficulties of prenatal diagnosis. Prenat Diagn. 2002;22(6):470–477
3. Izumi K, Krantz ID. Pallister-Killian syndrome. Am J Med Genet C Semin Med Genet. 2014;166C(4):406–413
4. Lu X, Phung MT, Shaw CA, et al. Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics. 2008;122(6):1310–1318
5. Salzano E, Raible SE, Kaur M, et al. Prenatal profile of Pallister-Killian syndrome: retrospective analysis of 114 pregnancies, literature review and approach to prenatal diagnosis. Am J Med Genet A. 2018;176(12):2575–2586
6. Joshi R, Myers E, Kokhanov A. Congenital disorders of red blood cells. Neoreviews. 2022;23(12):e813–e828
7. Cunniff C, Jones KL, Saal HM, Stern HJ. Fryns syndrome: an autosomal recessive disorder associated with craniofacial anomalies, diaphragmatic hernia, and distal digital hypoplasia. Pediatrics. 1990;85(4):499–504
8. Slavotinek A. Fryns Syndrome. 2007 Apr 18 [Updated 2020 Sep 17]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–Available from: https://www.ncbi.nlm.nih.gov/books/NBK1459/
9. Viehl L, Gaut JP, Dandamudi R, Davis, TK. Ambiguous genitalia in a newborn. Neoreviews. 2018; 19(8):e485–e489
10. Antonius T, van Bon B, Eggink A, van der Burgt I, Noordam K, van Heijst A. Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G > A(Arg366His) mutation. Am J Med Genet A. 2008;146A(4):496–499