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CC BY-NC-ND 4.0 · Journal of Fetal Medicine 2024; 11(04): 227-230
DOI: 10.1055/s-0045-1808250
Case Report

Fetal Exome Sequencing in Diagnosing Chondrodysplasia Punctata Associated with Maternal Systemic Lupus Erythematosus: A Case Report

Christina J. Miller 
1   Genetic Counseling Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
,
Kestutis Micke
2   Colorado Fetal Care Center, Children's Hospital Colorado, Aurora, Colorado, United States
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Abstract

Chondrodysplasia punctata (CDP) is a rare congenital disorder characterized by midface hypoplasia, stippled epiphyses, and limb shortening. Among the heterogeneous factors that cause CDP, maternal autoimmune conditions have caused 34 cases, including ours, to date. We describe a previously unreported case of CDP associated with maternal systemic lupus erythematosus (SLE). A 27-year-old G1P0 patient with a known history of SLE with anti-Ro/SSA autoantibodies was evaluated at our center at 21w1d. After reviewing fetal imaging and negative karyotype, microarray, and exome sequencing, our clinical team agreed upon establishing a clinical diagnosis of maternal SLE-associated CDP at 21 weeks' gestation. The combination of negative exome sequencing, karyotype, and chromosomal microarray analysis and relevant clinical findings enabled us to make the appropriate diagnosis at 21 weeks rather than in the third trimester or postnatally when additional phenotypic features became apparent. This earlier diagnosis provided the clinical team with time to assess additional recommended management and referrals and perhaps more importantly, provided the patient with additional time to consider her pregnancy options.


 

Keywords

fetal chondrodysplasia punctata - maternal SLE - systemic lupus erythematosus - exome sequencing - genetic testing - prenatal imaging

Introduction

Chondrodysplasia punctata (CDP) is a rare congenital disorder characterized by stippled epiphyses, Binder phenotype facies, and limb shortening.[1] [2] [3] Etiologies include inborn errors of metabolism, disruption in vitamin K metabolism, chromosomal disorders, maternal factors including autoimmune conditions, and exposures.[1] [4] [5]

To date, including our case, 34 instances of maternal autoimmune disorders causing CDP have been confirmed, 19 from systemic lupus erythematosus (SLE), 13 from mixed connective tissue disorder (MCTD), 1 from MCTD/scleroderma, and 1 from Sjogren disease.[2] [4] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] Maternal SLE is also associated with neonatal lupus, which can present with dermatologic, hematological, hepatobiliary, and cardiac manifestations.[23] [24] We present a previously unreported case of maternal SLE-associated CDP where excluding genetic causes enabled more timely clinical management.


 

Case Presentation

A 27 year old G1P0 patient was referred to our fetal care center at 18w1d after an ultrasound revealed short long bones, possible midface hypoplasia, and a resolved thickened nuchal translucency (2.9 mm) in a male fetus. The patient had a known history of SLE with anti-Ro/SSA autoantibodies, managed with hydroxychloroquine and belimumab. Teratogenic exposures were denied, family history was unremarkable, and consanguinity was denied.

At 21w1d, our center's fetal ultrasound and magnetic resonance imaging confirmed hypoplastic nasal bone, possible mild orbital hypoplasia with normal maxilla, and rhizomelic shortening of the long bones (shown in [Fig. 1]) with humerii and femurs lagging behind the overall size of the fetus (shown in [Table 1]). Fetal echocardiogram was normal.

Table 1

Fetal biometry

Measurement

21w1d

25w1d

29w2d

34w0d

Estimated fetal weight (EFW)

13%

11%

8%

6%

Biparietal diameter (BPD)

48%

50%

79%

48%

Head circumference

46%

53%

71%

49%

Abdominal circumference

44%

45%

17%

21%

Femur length (FL)

2%

(–3.0 SD)

< 1%

(–2.9 SD)

< 1%

(–2.8 SD)

< 1%

(no SD given)

Humerus length (HL)

1%

(–2.2 SD)

< 1%

(–2.8 SD)

< 1%

(–4.6 SD)

< 1%

(no SD given)

Abbreviation: SD, standard deviation.


Note: Fetal biometry on ultrasound at four time points during the pregnancy. Femur and humerus lengths are consistently lagging behind head and abdominal measurements.


Zoom
Fig. 1 (A) (top left) Ultrasound imaging from 21w1d demonstrating shortened humerus length. (B) (bottom left) Ultrasound imaging demonstrating shortened femur length. (C) (right) Ultrasound imaging demonstrating the Binder facial phenotype: orbital hypoplasia, flat nose, and convex upper lip.

Chorionic villus sampling at 12w2d at an outside facility showed normal fluorescent in situ hybridization, karyotype, and chromosomal microarray analysis. During pretest counseling for exome sequencing (ES), the patient expressed a desire to terminate the pregnancy if a genetic etiology was found. ES completed at 20w6d revealed no pathogenic, likely pathogenic, or uncertain variants.

After reviewing all findings and considering the maternal condition and past case reports, a clinical diagnosis of SLE-associated CDP was made at 21 weeks. The patient, counseled about the decreased likelihood for intellectual disability in the absence of genetic causes, continued the pregnancy.

An ultrasound at 34w0d, after the patient transferred care to another hospital, identified femoral stippling for the first time in the pregnancy and the persistence of shortened long bones ([Table 1]), further confirming CDP. Postnatal physical and radiological evaluation, including a skeletal survey, and neonatal lupus screening via plasmalogens were recommended.


 

Discussion

This case is the second reported instance of SLE-associated CDP where comprehensive genetic testing was pivotal in diagnosis.[11] Maternal SLE-associated CDP should be a diagnosis of exclusion. The absence of pathogenic, likely pathogenic, and uncertain variants allowed us to more confidently unify the diagnosis with the maternal history in the second trimester rather than later in pregnancy or postnatally when more clinical features become apparent.

Counseling on the anticipated phenotype and recurrence risks was challenging in this case. Genetic forms of CDP, like those associated with PEX5/7 and ARSE, are usually multisystemic with poor developmental outcomes, while maternal SLE-associated CDP seems to spare cognitive development.[1] [7] [9] [25] Four cases of fetal Binder phenotype without short long bones suggest variable expressivity.[26] The lack of an established mechanism linking maternal SLE to CDP made it difficult to accurately assess the risk of recurrence in future pregnancies. The occurrence of affected sibling pairs in four separate families suggests elevated recurrence risks.[6] [8] [14] [20]


 

Conclusion

We present this case to increase awareness of SLE-associated CDP and to emphasize the clinical power of negative ES. Negative ES facilitated a more confident diagnosis prior to the onset of pathognomonic epiphyseal stippling. This additional time allowed for genetic counseling regarding chances for intellectual disability, timely management decisions, and provided the patient more time to consider her pregnancy options.


 

 

Conflict of Interest

None declared.

Previous Presentations

Miller, C. & Micke, K (May 19, 2023). Utility of negative fetal exome sequencing in diagnosing chondrodysplasia punctata associated with maternal systemic lupus erythematosus: a case report. Poster presentation at Colorado Clinical and Translational Sciences Institute (CCTSI) Annual Spring Pediatric Research Poster Session, Aurora, CO. Miller, C. & Micke, K (March 16, 2023). Utility of negative fetal exome sequencing in diagnosing chondrodysplasia punctata associated with maternal systemic lupus erythematosus: a case report. Poster presentation at the Annual Conference of the American College of Medical Genetics, Salt Lake City, UT.


Patients' Consent

Written informed consent was obtained from the participant. The privacy rights of the participant were respected. Patient data and imaging were not published without written permission.


Statement of Conforming to Declaration of Helsinki

The work was conducted in accordance with the Declaration of Helsinki.


Authors' Contributions

C.M. contributed to conceptualization, data curation, project administration, visualization, writing–original draft, and writing–review and editing. K.M. contributed to conceptualization, data curation, project administration, resources, supervision, and writing–review and editing.



Address for correspondence

Christina Miller, MS, CGC
Center for Fetal Medicine and Reproductive Genetics, Brigham and Women's Hospital, Harvard Medical School
75 Francis St., Boston, MA 02115
United States   

Publication History

Article published online:
25 April 2025

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Zoom
Fig. 1 (A) (top left) Ultrasound imaging from 21w1d demonstrating shortened humerus length. (B) (bottom left) Ultrasound imaging demonstrating shortened femur length. (C) (right) Ultrasound imaging demonstrating the Binder facial phenotype: orbital hypoplasia, flat nose, and convex upper lip.