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Genotype-Phenotype Analysis of Interstitial Deletion of Chromosome 4q25q28.2: A Case Report  

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Interstitial Chromosome 4 Deletion 4q25q28.2 (OMIM #3764971) is a rare, de novo, 20,087 kbp deletion. Common phenotypes associated with microdeletions of relative similarity are loosely classified as 4q Deletion Syndrome in limited literature. 4q Deletion Syndrome is characterized by highly variable phenotypes that are dependent on the individual and the chromosomal region affected. The rarity and variability of this syndrome has resulted in difficulty establishing correlations of phenotypes. We report a case of an interstitial deletion of 4q25q28.2 in a patient born with several notable anatomic dysmorphisms and global milestone delays. The 4q25q28.2 region encodes for 61 genes that are primarily responsible for cardiac and neurological development. Notable deleted genes include PITX2 (OMIM #601542), ALPK1 (OMIM #607347), CAMK2D (OMIM #607708), and ANK2 (OMIM #106410).   

 

Case Presentation
We report a 6-year-old male born at 40 weeks to a 29-year-old G3P2 women, with the pregnancy complicated by prenatal hydronephrosis. His typically developing brother, now at age 12, had early hydronephrosis which resolved spontaneously. Neonatal course complicated by jaundice, umbilical hernia, and failed newborn hearing screen. Patient failed multiple following hearing screens; however, no assistive devices are needed. The patient presented to genetics at 5 years old with a height of 101.7 cm (2%ile), weight of 16.2 kg (8%ile), and head circumference of 53 cm (89%ile). Medical history is significant for global milestone delays, hypospadias, pes planus, dysplastic teeth and frenula, short stature, esotropia, hyperopia, left ptosis, tear-shaped pupil and relative macrocephaly. The patient presents with notable anatomic dysmorphisms including small fontanel, prominent forehead, low-set dysplastic ears, down-slanting palpebral fissures, small nares, small mouth, micrognathia, high-arched palate.

 

Diagnostic Workup
Microarray revealed a likely pathogenic 20,087 kbp deletion of 4q25q28.2. Family history contributes neurofibromatosis in a maternal uncle, cardiomyopathy in the maternal grandmother (deceased at 33 years). Whole exome analysis later revealed a maternal origin pathogenic variant in the WTN10A gene (OMIM #606268). Whole exome sequencing further confirmed the presence of the 4q25q28.2 deletion and its de novo origin. The WNT10A gene is associated with several clinical phenotypes of mostly autosomal inheritance, including selective dental agenesis type 4 (OMIM #150400), which may be contributing to his dysplastic teeth, though his mother denies a history of dental problems herself.

 

Treatment and Management
2 of 61 deleted genes are associated with ophthalmic problems, while 2 others are notable for cardio-vascular problems. The patient was referred to pediatric ophthalmology and pediatric cardiology for evaluations and baseline assessments.

 

Outcome and Follow-Up
The cardiologic assessment was negative for significance; however, the patient does require intermittent surveillance with a 2 yr. follow-up scheduled. The genetic findings otherwise did not impact his course of treatment.

 

Discussion
Deletions of the long arm of chromosome 4 are rare, with diverse phenotypic manifestations dependent on gene content and breakpoints. We present a case of an interstitial chromosome 4 deletion that mirrors some previously reported features, with the addition of others such as short stature, relative macrocephaly, hypospadias, and pes planus. Common phenotypes observed in limited literature include developmental delay, digital, skeletal, and cardiac anomalies, and dysmorphic features. Previously reported cases with overlapping deletions have noted renal dysplasia, progressive renal failure, and clinical features of Reiger’s Syndrome.

 

Conclusion
This case contributes to the literature on correlated phenotypes for varying presentations of 4q deletions.   

 

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