Case Report: Long-term follow-up in ulnar-mammary syndrome caused by novel TBX3 variants: a case series with longitudinal endocrine follow-up

Background Ulnar-mammary syndrome (UMS; MIM 181450) is a rare autosomal-dominant disorder with incomplete penetrance affecting multiple body systems, including the upper limbs, apocrine glands, teeth, hair, and genitals. Long-term natural history data are scarce, as most reported cases lack sustained clinical follow-up. This report describes two pediatric patients with UMS harboring novel TBX3 variants, with a focus on the endocrine trajectory in one case. Case description We report two male patients diagnosed with UMS at 12 years of age. Patient 1 (P1) was previously reported in a Chinese-language case description at his initial presentation (Wang et al., 2020); the present report extends that case with longitudinal data through age 16 and adds a second patient. P1 presented with slow growth velocity, delayed puberty, and characteristic dysmorphic features including mammary gland hypoplasia and apocrine glands. Genetic testing identified a de novo frameshift variant in TBX3 (c.711del p.N238Mfs*4). He received recombinant human growth hormone (rhGH) therapy for approximately 2.5 years. On longitudinal follow-up until age 16, GH secretory responses normalized on repeat testing and pituitary hypoplasia was no longer evident on MRI. The initial suspicion of isolated hypogonadotropic hypogonadism (IHH) was revised to constitutional delay of growth and puberty (CDGP) after spontaneous puberty commenced at age 15 and progressed. Patient 2 (P2) presented with pubertal delay and mammary gland hypoplasia without facial dysmorphism, and was found to have a de novo splice-site variant (c.658-3C>G). A minigene assay confirmed that this variant disrupts normal mRNA splicing, generating two aberrant transcripts that are predicted to result in loss of TBX3 function. He had been treated with rhGH at an outside hospital from age 10 years and 10 months for approximately one year; repeat GH stimulation testing at our institution after a > 5-month wash-out period showed a normal peak GH of 14.1 μg/L. rhGH was re-initiated due to documented growth arrest, with progressive dose titration and a partial growth response observed through age 14 years and 8 months (height 161.7 cm). Conclusion This case series expands the mutational spectrum of UMS with two novel TBX3 variants and provides longitudinal observational data suggesting that GH deficiency and pituitary hypoplasia in UMS may not be permanent in all patients, and that some cases of presumed IHH may represent CDGP. These findings emphasize the potential value of long-term monitoring in UMS to better characterize disease evolution and avoid premature conclusions about endocrine prognosis. The main limitations are the retrospective, two-case design.