Comprehensive Analysis of Disease Spectrum and Mortality in Sanjad-Sakati Syndrome: An International Rare Disease...

Sanjad-Sakati syndrome (SSS), also known as hypoparathyroidism-intellectual disability-dysmorphism syndrome, is a rare autosomal recessive disorder caused by a TBCE founder mutation. The full disease spectrum remains poorly understood.

To comprehensively analyze growth, phenotype, endocrine manifestations, and mortality in a large multicenter SSS cohort.

Clinical and genetic data were collected from 135 individuals across centers in the Gulf region using a REDCap survey.

The median age at inclusion was 9.1 years (range: birth-30 years; 50.3% female). The homozygous TBCE founder mutation (c.155_166del; p.Ser52_Gly55del) was detected in all genetically tested individuals (n = 68). Intrauterine growth restriction (mean birth weight -3.0 SD, length -3.3 SD) and dysmorphic features were universal. Postnatal growth showed severe failure to thrive during infancy, followed by persistently low height z-scores (-7 to -8). Endocrine features included hypoparathyroidism in all patients, primary hypothyroidism (16.5%), hypoglycemia (27.8%), non-autoimmune insulin-dependent diabetes (1.6%) and pituitary hormone deficiencies. Other findings included developmental delay (100%), hypocalcemic seizures (64.2%), tetany (53.3%), nephrocalcinosis (62.1%), gastroesophageal reflux (29.1%), and recurrent respiratory (63.7%) and bacterial infections (53.8%). Antibiotic prophylaxis was used in 35% of patients. Kaplan-Meier analysis estimated a median survival of 27.2 years, with respiratory failure causing 84% of deaths (21/25). The estimated overall survival at an age of 18 years was 62.4%.

This largest reported SSS cohort highlights the high prevalence of associated endocrine, respiratory, and gastrointestinal manifestations, with respiratory failure as the leading cause of death. These data support the need for multidisciplinary care guidelines.