Hypogonadotropic hypogonadism and pituitary hypoplasia as recurrent features in Ulnar-Mammary syndrome

Abstract

Ulnar-mammary syndrome (UMS) is characterized by ulnar defects, and nipple or apocrine gland hypoplasia, caused by TBX3 haploinsufficiency. Signs of hypogonadism were repeatedly reported, but the mechanisms remain elusive. We aim to assess the origin of hypogonadism in two families with UMS. UMS was suspected in two unrelated probands referred to an academic center with delayed puberty because of the evident ulnar ray and breast defects in their parents. Clinical, biochemical and genetic investigations proved the existence of congenital normosmic IHH (nIHH) associated with pituitary hypoplasia in the two probands who were heterozygous for novel TBX3 pathogenic variants. The mutations co-segregated with delayed puberty, midline defects (nose, teeth and tongue anomalies) and other variable features of UMS in the two families (absent axillary hairs and nipple hypoplasia, asymmetrical features including unilateral ulnar or renal abnormalities). The combined analysis of these findings and of the previous UMS reports showed delayed puberty and other signs of hypogonadism in 79 and 37% of UMS males, respectively. Proband 1 was followed up to adulthood with persistence of nIHH. In conclusion, UMS should be suspected in patients with delayed puberty and midline defects, including pituitary hypoplasia, in the presence of mild cues for TBX3 mutation, even in the absence of limb malformations. In addition, TBX3 should be included among candidate genes for congenital nIHH.

Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset

“…Recent studies suggest that phase separation of transcription factors could provide a critical biophysical basis for the transcriptional control of gene expression ( 33 , 34 ). To gain insight into the molecular pathological mechanism of delayed puberty in UMS patients, we selected four genetic variants of TBX3 associated with impaired sexual maturation in human beings for further phase separation analysis ( 14 , 20 , 35 ). Among the selected genetic mutations, three of them (L143P, Y149S, and S190R) occurred in T-box domain that is evolutionarily conserved in different species, and the other nonsense mutation (Q475X) introduced a termination codon in the activation domain of hTBX3 ( Fig.…”

“…As aforementioned, UMS patients carrying TBX3 mutations frequently display delayed puberty onset and genital hypoplasia (14,20). To determine whether Tbx3 loss of function in KNDy neurons recapitulates the phenotypes observed in UMS patients, we analyzed the timing of puberty onset and performed fertility assay in male and female TKO mice.…”

“…In marked contrast to precocious puberty, idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (defined as Kallmann syndrome) is characterized by delayed or absent puberty, and frequently caused by the defective migration of GnRH neurons into the hypothalamus from nasal placode ( 8 , 13 ). Loss-of-function mutations in TBX3 have recently been reported to cause congenital IHH with normal sense of smell ( 14 ), hinting at its potential roles in processes involved in puberty onset such as the specification of KNDy neuronal identity and regulation of GnRH neuronal migration, although whether and how this occurs remains unknown.…”

“…In humans, TBX3 mutations have been linked to ulnar-mammary syndrome (UMS), an autosomal dominant disease with variable penetrance featured by shortened forelimbs, mammary and apocrine gland hypoplasia, and genital anomalies ( 19 ). Although patients with TBX3 mutations have long been found to display a consistent feature of delayed puberty ( 20 ), TBX3 has not been regarded as a candidate gene for normosmic IHH until recently ( 14 ), raising the possibility that it is directly involved in the pathogenesis of delayed puberty onset in UMS patients.…”

The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

“…Variants in the TBX3 gene, which encodes for a member of the T-box transcription factors, are associated with ulnar-mammary syndrome, whose symptoms include hypogonadism, delayed puberty, ulnar ray defects and hypoplasia of nipples [231]. Heterozygous variants of TBX3 have also been recently described in two unrelated families with normosmic CHH and pituitary hypoplasia [232]. However, the role of TBX3 in GnRH neuron physiology has not yet been elucidated.…”