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From Short Stature to Facioscapulohumeral Muscular Dystrophy-2: The Benefits and Challenge of Broad-Based Sequencing

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Here we present a case of a pediatric patient who received a co-occurring ultra-rare genetic diagnosis: IGF1R-related disorder, explaining her clinical history, alongside a diagnosis of facioscapulohumeral muscular dystrophy-2 (FSHD2). Reports of patients affected by heterozygous pathogenic IGF1R variants are limited and we are not aware of any reports of FSHD2 in the pediatric setting. Recommendations for screening and management are limited by the limited available evidence.

Case Presentation
 A 17-month-old female presented for genetic evaluation of proportional short stature, failure to thrive (FTT), feeding difficulties with associated oral-facial weakness, and mild motor delay. Her history was notable for use of intracytoplasmic sperm injection (ICSI) at conception, advanced paternal and maternal age, and intrauterine growth restriction (IUGR) throughout the pregnancy. Exam by a medical geneticist revealed a subtly-bossed forehead, low posterior hairline, prominent eyes, thin upper lip, small chin, and 5th-finger clinodactyly.

Diagnostic Workup
Chromosomal microarray (negative), Russel-Silver syndrome methylation (negative), and trio exome sequencing were conducted. De novo likely pathogenic variants in both IGF1R (NM_000875.3:c.1445A>G) and SMCHD1 (NM_015295.2:c.3656dup) were reported. Despite initially declining secondary findings, the family elected to pursue molecular evaluation of facioscapulohumeral muscular dystrophy, which identified a non-contracted 4q35A allele and D4Z4 hypomethylation (25%). This led to a diagnosis of autosomal dominant IGF1R-related disorder and presymptomatic, digenic FSHD2. Her creatine kinase (279 U/L) and insulin growth-like factor binding protein 3 (5.3 mg/L) have since been identified as elevated.

Treatment and Management
We recommended continuing supportive management, establishing care with pediatric endocrinology, and consultation with a neurologist to evaluate for and manage features of FSHD2 as concerns arise.

Outcome and Follow-Up
The family welcomed a unifying diagnosis for the patient’s history and ultimately desired all available information about her risk for FSHD2, but their genetic evaluation created more questions and care needs than it addressed. Since her diagnosis the patient has had an unremarkable echocardiogram. She continues to be managed by a multidisciplinary feeding clinic and developmental therapist (speech, physical, occupational, and feeding). A g-button was recently placed to support nutritional and caloric goals without forcing oral feeding. Bilateral hip dysplasia was incidentally identified during her g-button pre-operative screening. Her local endocrinology team has advised to delay consideration of growth hormone (GH) therapy until age three. The family has arranged for a second opinion from a pediatric endocrinologist with a special interest in IGF1R-related disorders in November of 2024. Her physical therapist has recommended treatment plan adjustments if her oral and facial weakness is attributable to FSHD2. She is scheduled for a multidisciplinary evaluation with an FSHD specialty neurologist in January of 2025 and a local neurologist in February of 2025. 

Discussion
There are case reports of improvement of growth parameters through GH supplementation in patients with IGF1R-related disorder, but this evidence is limited by the small number of patients, varied response to GH without genotype-phenotype evidence, and admixture of patients with biallelic pathogenic variants. While there are existing natural history data and management guidelines for FSHD2, characterization has thus far been limited to a teen- to adult-onset neuromuscular weakness with prognostication further complicated by reduced penetrance and variable progression.

Conclusion
This case highlights a need for additional translational research into the utility of GH in patients with heterozygous pathogenic IGF1R variants. The reporting of an SMCHD1 variant in a pediatric patient without neuromuscular weakness also raises questions about laboratory classification of primary versus secondary findings. Finally, the unresolved questions of appropriate management in this case underscores the unique challenges of providing evidence-based care at the intersection of ultra-rare diagnoses, co-occurring diagnoses, and molecular diagnoses that represent expansions of the existing phenotypic spectrum.

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