PUF60 loss-of-function with normal cognition should be considered in the differential diagnosis of Klippel-Feil syndrome.

Klippel-Feil syndrome (KFS) has a genetically heterogeneous phenotype with six known genes, exhibiting both autosomal dominant and autosomal recessive inheritance patterns. PUF60 is a nucleic acid-binding protein, which is involved in a number of nuclear processes, including pre-mRNA splicing, apoptosis, and transcription regulation. Pathogenic variants in this gene have been described in Verheij syndrome due to either 8q24.3 microdeletion or PUF60 single-nucleotide variants. PUF60-associated conditions usually include intellectual disability, among other findings, some overlapping KFS; however, PUF60 is not classically referred to as a KFS gene. Here, we describe a 6-year-old female patient with clinically diagnosed KFS and normal cognition, who harbors a heterozygous de novo variant in the PUF60 gene (c.1179del, p.Ile394Serfs*7). This is a novel frameshift variant, which is predicted to result in a premature stop codon. Clinically, our patient demonstrates a pattern of malformations that matches reported cases of PUF60 variants; however, unlike most others, she has no clear learning difficulties. In light of these findings, we propose that PUF60 should be considered in the differential diagnosis of KFS and that normal cognition should not exclude its testing.

Differential Endocrine and Metabolic Effects of Testosterone Suppressive Agents in Transgender Women.

OBJECTIVE: Suppression of testosterone secretion and/or action in transgender women using cyproterone acetate (CPA), spironolactone, or gonadotropin-releasing hormone analogues (GA) is achieved through various mechanisms. Our objective was to characterize possible differential effects of these compounds on metabolic and endocrine variables. METHODS: We conducted a historic cohort study of transgender patients treated in a tertiary referral center. A longitudinal analysis of treatment naïve patients and a cross-sectional analysis of the whole cohort at the last visit was carried out. RESULTS: Among 126 transgender women (75 treatment-naïve), CPA was the predominant androgen suppressive therapy (70%), followed by spironolactone (17.6%), and GA (10.2%). Among those who were treatment-naïve, the increase in serum prolactin levels over baseline was greater at 3 months following CPA initiation (mean change 397 ± 335 mIU/L) than following spironolactone (20.1 ± 87 mIU/L) or GA initiation (64.6 ± 268 mIU/L; P = .0002). Prolactin levels remained higher in the CPA-treated group throughout follow-up, irrespective of estradiol levels, which were similar between the groups. A worse metabolic profile was associated with treatment with CPA than with spironolactone or GA. In the CPA compared to the spironolactone and GA groups, high-density lipoprotein-cholesterol levels were lower (47.1 ± 10.4, 54.4 ± 12.2, and 60.3 ± 13, respectively; P = .0076), while body mass index levels (24.3 ± 5, 21.7 ± 2.3, and 20.7±3.1 kg/m2; P = .03), and systolic (117 ± 12.1, 109 ± 12.2, and 105 ± 13.3mm Hg; P = .01) and diastolic (74 ± 9, 65.6 ± 5.5, and 65.4 ± 11 mm Hg; P = .0008) blood pressure levels were higher at the last visit. CONCLUSION: Treatment of transgender women with CPA was associated with hyperprolactinemia and a worse cardiovascular risk profile than treatment with spironolactone or GA. ABBREVIATIONS: BMI = body mass index; CPA = cyproterone acetate; E2 = estradiol; FSH = follicle-stimulating hormone; GA = gonadotropin-releasing hormone analogues; LH = luteinizing hormone.