Background: SHORT syndrome is a multisystemic disorder, the acronym standing for Short stature, Hyperextensibility, Hernia, Ocular depression, Rieger anomaly, and Teething delay. It is a rare autosomal dominant condition caused by pathogenic variants in PIK3R1, a critical regulator of the PI3K/AKT signaling pathway. With fewer than 50 cases reported worldwide, early recognition and accurate diagnosis remain particularly challenging.Case Presentation: We report a 19-month-old male with growth restriction first noted in the third trimester of pregnancy. The pregnancy was otherwise uneventful, and delivery occurred at 37 weeks of gestation by spontaneous vaginal birth, without need for resuscitation.Birth weight was -2.38 SDS, length -2.96 SDS, and head circumference -1.23 SDS, classifying him as small for gestational age.The neonatal period was notable for jaundice requiring phototherapy. No other complications, such as hypoglycemia, were observed. Newborn screening was unremarkable except for failed auditory testing.At birth, dysmorphic features were evident, including triangular facies, prominent forehead, midface hypoplasia and micrognathia.He is the second child of healthy, non-consanguineous parents, with no relevant family history of endocrine, metabolic, or genetic disorders. Mid-parental target height corresponds to 0.59 SDS.At 15 days of age, due to his feeding difficulties, poor weight gain, and the presence of dysmorphic features, he was referred for neonatal evaluation. Multiple hospitalizations ensued for nutritional optimization, briefly requiring orogastric tube feeding and high-caloric nutrition supplementation. He was also referred for speech and occupational therapy.An extensive investigation excluded chronic disease. Hematological, renal, hepatic, thyroid, and adrenal function were normal. Screening for malabsorption, including celiac disease, was negative. IGF-1 and IGF-BP3 were within the reference range. Metabolic assessment - including acylcarnitines, urinary organic acids, sulfite test, and amino acid profiling plasma and urine - was unremarkable. Imaging (cranial ultrasound, abdominal ultrasound, echocardiography and renal ultrasonography) showed no abnormalities other than mild bilateral calyceal prominence.Silver-Russell syndrome was initially suspected; however, the MS-MLPA study of the 11p15 region and the study for chromosome 7 disomy did not identify any significant alteration. Subsequently, an exome study was requested, which identified a heterozygous pathogenic variant, c.1945C>T p.(Arg649Trip), in the PIK3R1, establishing the diagnosis of SHORT syndrome. The patient had since been followed by a multidisciplinary team (neonatology, otorhinolaryngology, genetics, ophthalmology, endocrinology, pediatric gastroenterology, and nutrition).After the most recent follow-up, growth remained impaired: weight -4.34 SDS, length -3.41 SDS, and head circumference -2.13 SDS.Current phenotype includes generalized paucity of facial fat, partial lipodystrophy (upper limbs and buttocks), and delayed dentition. No hyperextensibility or hernias were observed. Complications have included glaucoma and bilateral sensorineural hearing loss. Neurodevelopmental milestones remain age-appropriate. Recent laboratory evaluation showed no evidence of glucose intolerance, insulin resistance, or hyperglycemia.Learning Points: SHORT syndrome is an ultra-rare genetic disorder, and its heterogeneous presentation makes early diagnosis particularly challenging. Early recognition enables timely surveillance for complications. A multidisciplinary, long-term follow-up approach is essential to optimize growth, development, and quality of life in affected patients.This case contributes to the limited number of reports worldwide, expanding knowledge of the phenotypic spectrum of SHORT syndrome.
