Two recent reports describe a new syndrome of intellectual disability, short stature, microcephaly, and young onset diabetes or disturbed glucose metabolism in association with inactivating mutations in the TRMT10A gene. We investigated the clinical spectrum presented by a 17-year-old female with a homozygous contiguous gene deletion involving the TRMT10A gene. From infancy, she presented with failure to thrive and microcephaly. Puberty was characterized by a slow and an inconsistent course of progression. Concomitantly, gonadotropin levels fluctuated between low and high levels which were compatible with gonadal failure. Unlike the previous reports, the patient had ketoacidosis at onset of diabetes and islet cell autoantibodies. Nevertheless, glycemic control was excellent (HbA1C 5.0%-6.2%). RT-PCR and Western blot analysis demonstrated a complete abolishment of TRMT10A mRNA and its translated protein. In order to elucidate the nature of diabetes in this patient, endogenous insulin secretion and glycemic control were evaluated by a glucagon stimulation test and continuous glucose monitoring both during insulin treatment and off therapy. Endogenous insulin secretion still persisted 22 months after onset of diabetes and relatively normal glucose levels were kept over 3 days without insulin treatment. The fluctuating course of puberty and diabetes may reflect intermittent apoptotic damages due to sensitization of the relevant cells to various stress agents in the absence of functional TRMT10A.

Objective: Characterization of pubertal progression is required to prevent unnecessary intervention in unsustained or slowly progressive (SP) precocious puberty (PP), while delivering hormonal suppression in rapidly progressive (RP) PP. We aimed to assess the diagnostic value of first-voided urinary LH (ULH) compared with GNRH-stimulated gonadotropins in differentiating these forms of PP. Methods: A total of 62 girls with PP underwent both GNRH stimulation and ULH assay. Fifteen girls with peak LH R10 IU/l started treatment immediately, whereas the other 47 girls were evaluated after 6 months for pubertal advancement, height acceleration, and bone-age maturation. Based on these criteria, the participants were assigned to five subgroups: pubertal regression, no progression or progression by one, two or three criteria. The first three subgroups were defined as SP-PP (nZ29), while the other two subgroups were defined as RP-PP (nZ18). An additional 23 prepubertal girls were evaluated for ULH. Results: ULH but not serum gonadotropins could distinguish girls with two and three criteria from less progressive subgroups. By comparison with SP-PP (i.e. regression group and groups 0 and 1), those with RP-PP (group 2C3) had lower peak FSH (9.28G2.51 vs 12.57G4.30; PZ0.007) and higher peak LH:FSH ratio (0.42G0.30 vs 0.22G0.12; PZ0.022) and ULH (1.63G0.65 vs 1.05G0.26 IU/l; P!0.001). Based on receiver operating characteristics analysis, a ULH cutoff of 1.16 IU/l had a better sensitivity (83%) and positive and negative predictive values (65 and 88% respectively) than the other two parameters, with a specificity of 72%. Conclusions: ULH assay is a noninvasive, reliable method that can assist in the distinction between SP-and RP-PP.

Suppressed basal and post-GnRHa LH levels indicate adequate suppression of puberty. Clinical breakthroughs during treatment are transient and resolved spontaneously.

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