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Short Stature and Partial Lipodystrophy along with Hypersomnolence and PCOS: Rarity and Phenotypic Expansion of SHORT Syndrome

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
SHORT syndrome (short stature, hyperextensibility, ocular depression, Rieger anomaly, and teething delay) is associated with pathogenic monoallelic loss of function variants in the PIK3R1 gene. SHORT syndrome is rare with around 40 affected individuals reported so far. Clinical manifestations include intrauterine growth delay, distinctive facial gestalt, partial lipodystrophy involving face, chest and upper extremities, sensorineural hearing loss, and insulin resistance.  Monoallelic gain-of-function leads to immunodeficiency with lymphoproliferation, and biallelic loss-of-function variants results in agammaglobulinemia. We describe a family with SHORT syndrome with novel clinical manifestations that expands the phenotypic spectrum in this rare disorder.

Methods:
Chart review and prospective evaluation of a family diagnosed with SHORT syndrome.

Results:
Case Presentation: 

A 22-year-old female presented for evaluation of inherited causes for delayed puberty and short stature. Past medical history is notable for intrauterine growth restriction and difficulty to gain weight during childhood. The patient was clinically suspected to have Silver-Russell syndrome during early childhood in view of the facial features and failure to thrive; however, this was not confirmed molecularly. Growth hormone (GH) injections were tried for around a year at age 4 without benefit. She did not attain puberty until age 15 that warranted initiation of hormonal pills with which she experienced infrequent breakthrough menstrual cycles at age 21. She also underwent breast augmentation surgery. Medical history is also notable for hypersomnolence, several missing adult teeth, and progressive atrophy of facial subcutaneous fat.



Family history revealed that her father and a sister exhibited short stature and similar facial features. Additionally, father was diagnosed with glaucoma and diabetes in his 30s, and sister displayed hypersomnia and progressive facial fat atrophy that required jaw reconstruction. 



Physical exam revealed height of 154.5 cms and weight of 40.2 kgs. Distinctive facial features with triangular facies, deep set eyes, pointed nasal tip and hanging columella were noted, along with sparse axillary and pubic hair. Dental assessment revealed several missing adult teeth.



Diagnostic Workup: 

Pelvic ultrasound and endocrine evaluation were consistent with polycystic ovarian syndrome. Comprehensive sleep study was consistent with idiopathic hypersomnia. Bone age was normal. Past genetic evaluation included normal female 46 XX karyotype, normal chromosomal microarray and a noncontributory targeted testing with hypogonadotropic hypogonadism gene panel. Eye exam indicated astigmatism. Echocardiogram and renal ultrasounds were normal.  

 

Whole genome sequencing as Trio was completed and identified a heterozygous paternally inherited pathogenic variant in PIK3R1 (c.1960C>T p.Gln654Ter), confirming the diagnosis of autosomal dominant SHORT syndrome.



Treatment and Management: 

Due to the diverse manifestations of SHORT syndrome, the need for periodic surveillance and multidisciplinary follow-up was emphasized. Endocrinologic monitoring was planned for progression of partial lipodystrophy, insulin resistance, diabetes, thyroid abnormalities, and menstrual irregularities. GH injections are contraindicated in view of possible exacerbation of insulin resistance.

Conclusion:
This case highlights the clinical presentation of SHORT syndrome as a rare genetic condition that should be considered when assessing patients with similar facial features and constellation of these clinical features. A thorough family history aids evaluation. Comprehensive genetic evaluation with whole exome/genome sequencing is essential to identify rare disorders. SHORT syndrome also expresses phenotypic overlap with several disorders including Silver-Russell syndrome. This case underscores an intriguing association between SHORT syndrome and menstrual irregularities with PCOS, which has been noted in a limited number of case reports. Also, hypersomnia has not been described so far in literature in individuals with SHORT syndrome. Further research is needed to better understand this relationship and the possible pathways involved.

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