Ulnar-Mammary Syndrome (TBX3)

Autosomal dominant developmental disorder caused by heterozygous loss of function of TBX3: postaxial (ulnar) defects of the upper limb, mammary, nipple and apocrine hypoplasia, hypogonadotropic hypogonadism with pituitary hypoplasia, growth hormone deficiency and midline defects, with highly variable expressivity and forms without limb or breast involvement (“TBX3-related disorder”). Includes the diagnostic and therapeutic approach to longitudinal ulnar deficiency (ulnar club hand) of all causes.

Literature and regulatory information updated: 7 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Initial clinical descriptions

The association between absence of digits on the ulnar side and breast hypoplasia was recorded in 1882 by Gilly, in a woman with breast hypoplasia, inability to breastfeed and absence of the ulna and of the third, fourth and fifth digits, according to Smith's Recognizable Patterns of Human Malformation, which cites the original description [15]. The same book attributes to Pallister and colleagues, in 1976, the description of a pleiotropic dominant mutation affecting skeletal, sexual and apocrine-mammary development, and to Schinzel, in 1987, the consolidation of the entity [15]. The review by Halperin and Weiss places the first description of the syndrome by Albert Schinzel in 1973, in a Swiss family with ulnar ray defects, micropenis, delayed puberty and obesity, published in 1987 [4]. OMIM dates to 1973 Schinzel's report of a Swiss family in which the proband, his brother, father and nephew had ulnar ray defects, a small penis, delayed puberty and obesity, the proband and father also anal atresia, the proband pyloric stenosis and the father a congenital subglottic laryngeal web; Temtamy and McKusick included this family in their compendium of hereditary hand malformations, in 1978, under the name Schinzel syndrome [10]. In the same period, Pallister and colleagues (1976) described eight affected individuals in three generations, mostly women, with anomalies of the ulnar rays, breasts, axillary apocrine glands, teeth, palate, spine and urogenital tract, and Gonzalez and colleagues (1976) a mother and son with absence of body odour and axillary sweating, absence of breast tissue in the mother, unilateral renal agenesis and postaxial polydactyly; Hecht and Scott (1984) described a mother and daughter with absence of ulnar rays 3 to 5, absent ulna, short and bowed radius, pyloric stenosis and bilateral inguinal hernias [10]. The two attributions of priority therefore refer to distinct events: the isolated case of 1882 and the familial syndromic delineation of the 1970s.

In 1987, Schinzel, Illig and Prader described four men from three generations with defects of the ulnar rays of the hands and fibular rays of the feet, growth and pubertal delay, obesity, hypogenitalism, reduced sexual activity and hypoplasia of the nipples and apocrine glands with reduced perspiration; in isolated cases there was pyloric, anal and subglottic stenosis [7]. The authors then counted 12 published patients in three other families and proposed autosomal dominant inheritance with complete penetrance and variable expression [7]. In the same year, Schinzel published in the Journal of Medical Genetics the description under the name “ulnar-mammary syndrome” [27].

In 1996, Bamshad, Root and Carey described 33 affected members of a six-generation family from Utah, a number greater than the sum of all cases published until then [16]. This family defined the range of expression: in the limb, from hypoplasia of the terminal phalanx of the fifth finger to complete absence of the ulna and of digits 3 to 5, or posterior digital duplications with or without contralateral deficiency; in the apocrine glands, from reduced axillary sweating with normal breasts and lactation to absence of the breasts and of axillary sweating; and also ectopic or absent teeth, delayed puberty in affected men, reduced axillary hair in both sexes and imperforate hymen in some women [16]. The locus was mapped to 12q23-q24.1 [16]; linkage analysis gave a LOD score (logarithm of the odds) of 6.21 with marker D12S79, in a 21 cM region overlapping that of the Holt-Oram syndrome locus, and a common ancestor was later identified between this Utah family and the Pallister family [10]. Franceschini and colleagues (1992) described ectopic upper canines and a cleft hand due to absence of the fourth ray, and suggested, as Lenz had in 1980, that split hand with aplasia of the ulna was the same entity [10].

1.2. Identification of TBX3 and molecular milestones

In 1997, Bamshad and colleagues identified variants in TBX3, a gene of the T-box family, in two families (a single-nucleotide deletion and a splicing variant), both predicted to cause haploinsufficiency [28]. The authors noted that the defects of UMS affect the posterior elements of the limb, whereas variants in TBX5, a related gene linked on the same chromosome, cause the anterior defects of Holt-Oram syndrome, and proposed that the two genes acquired complementary functions in upper limb patterning after diverging from a common ancestral gene [28]. In 1999, the same group completed the coding sequence of TBX3, which encodes a protein of 723 residues, 255 of which derive from exons identified at that time, described alternative transcripts, one with an interrupted T-box, and found new variants in all eight families studied, five of them downstream of the T-box domain [6].

The subsequent milestones were the demonstration of haploinsufficiency in a Turkish family of 10 affected individuals with an insertion truncating the protein near its start [29], the first genomic deletion of 1.28 Mb at 12q24.21 including TBX3 as the only known gene [18], the description of pituitary and cardiac conduction anomalies [30], the characterisation of normosmic hypogonadotropic hypogonadism with pituitary hypoplasia as a recurrent feature [13], the first prenatal diagnosis [14] and the description of families without limb or breast defects, identified through hypogonadism and bladder anomalies [31].

1.3. Nomenclature

The name “ulnar-mammary syndrome” highlights the two territories most affected, the ulnar ray and the mammary gland [32]. The designation “síndrome cúbito-mamário”, used by Orphanet in Portuguese, applies European Portuguese anatomical terminology (“cúbito” instead of “ulna”) [2]. Halperin and Weiss proposed in 2026 the designation “TBX3-related disorder”, since the spectrum includes individuals with involvement of a single system, such as isolated hypogonadism, and individuals without clinical signs [4]. “Ulnar-mammary syndrome” (UMS) is used here for the clinical picture and “TBX3-related disorder” when the atypical forms are to be included.

1.4. Definition of the entity

UMS is defined by the presence of a heterozygous pathogenic or likely pathogenic variant in TBX3, or of a deletion including TBX3, in an individual with one or more of the following manifestations: postaxial upper limb defects, mammary, nipple or apocrine hypoplasia, hypogonadism, midline defects or growth hormone deficiency [4, 13]. No formal clinical criteria have been published. Contiguous deletions and duplications encompassing TBX3 and TBX5 give a phenotype combined with Holt-Oram syndrome [33, 34].

1.5. Longitudinal ulnar deficiency (ulnar club hand)

Longitudinal ulnar deficiency, also called ulnar hemimelia or ulnar agenesis/dysplasia, is a spectrum of osteoarticular, musculotendinous and neurovascular anomalies of the entire ulnar side of the upper limb, generally with preservation of the most radial structures (thumb and index finger) [26]. In severe forms, the forearm, wrist and hand deviate to the ulnar side and backwards (“ulnar club hand”), with partial or total limitation of elbow, forearm and wrist mobility, which may amount to ankylosis. Hypoplasia extends to the whole limb: the ulna ranges from partial hypoplasia to complete absence with humeroradial synostosis, the radius is often short and bowed posteriorly, the humerus is short and internally rotated, the carpus deviates and translates to the ulnar side, and the 4th and 5th rays are absent or hypoplastic, sometimes also the 3rd; the flexor muscles of the fingers and wrist and the hypothenar muscles may be absent, as may the ulnar nerve and artery, and the skin of the anterior aspect of the elbow may form a pterygium [26]. Preservation of the pinch between thumb and fingers generally gives the hand satisfactory function. UMS is one of the causes, and the most important among the syndromic ones; the others are in section 6.4. In the international Oberg, Manske and Tonkin (OMT) classification, ulnar deficiency belongs to the malformations due to a defect of differentiation of the radioulnar (preaxial/postaxial) axis of the limb [26].

2. Molecular Genetics and Pathophysiology

2.1. The TBX3 gene and protein

TBX3 is located at 12q24.21, immediately adjacent to TBX5 [2]. The MANE Select transcript is NM_005996.4 (transcript variant 1), with 7 exons and a protein of 723 amino acids (NP_005987.3) [4, 5, 9]. There is an alternative exon, exon 2a, whose inclusion gives transcript variant 2 (NM_016569), 60 nucleotides and 20 amino acids longer; TBX3 and TBX3+2a are the predominant isoforms, and part of the literature numbers variants on NM_016569 [3, 13, 14]. The protein contains the DNA-binding T-box domain, encoded by exons 1 to 3 and part of exon 4, a nuclear localisation signal, two repressor domains (R1 and R2) and an activation domain [3, 9, 14].

The T-box domain binds a partially palindromic element, the T element, or a half-site, in the regulatory regions of target genes [2, 4]. TBX3 acts mainly as a transcriptional repressor, but also interacts with splicing factors, binds RNA with TBX motifs and regulates alternative splicing; variants found in patients with UMS disrupt this function in experimental models [35]. TBX3 is expressed from the morula onwards, takes part in maintaining the pluripotency of embryonic stem cells and has roles in cell fate determination and organogenesis [4].

2.2. Developmental functions

In the limb, TBX3 takes part in the specification of posterior mesoderm and in the dorsoventral axis and is required to establish the posterior boundary of the limb bud [4, 13]. In the Bamshad family, the posterior elements of the forearm, wrist and hand were affected and the anterior ones showed normal growth and development, with disturbed patterning along the proximodistal, anteroposterior and dorsoventral axes [16]. Dorsalisation or ventral duplication of the nail of the fifth finger, described in several families, reflects involvement of the dorsoventral axis [9, 15, 32].

In the mammary gland, TBX3 is expressed in the ventrolateral body wall, between the fore- and hindlimb buds, where the mammary line forms; it induces and maintains the mammary placode and, with TBX2, contributes to branching of the mammary gland and lung [2, 4]. It is also required for the hormone-sensing cell lineage of the mammary epithelium [13]. The epithelial-mesenchymal interaction that TBX3 regulates in the limb bud recurs in the development of the breast, teeth and external genitalia [13].

In the hypothalamic-pituitary axis, TBX3 is expressed in the infundibulum and Rathke's pouch; in Tbx3-null mice, the infundibulum does not form, Rathke's pouch degenerates and the pituitary is hypoplastic, through derepression of the sonic hedgehog pathway in the ventral diencephalon and deficient FGF signalling from the infundibulum, according to Galazzi and colleagues, who cite the study by Trowe and colleagues [13]. TBX3 also takes part in the differentiation of the hypothalamic neurons that regulate the onset of puberty and of the melanocortinergic neurons that control appetite and energy expenditure, according to the review by Halperin and Weiss [4].

In the heart, TBX3 is expressed in the myocardium of the atrioventricular canal, the sinoatrial and atrioventricular nodes, the bundle of His and the proximal bundle branches [3, 22]. In mice, quantitative reduction of Tbx3 causes sinus node dysfunction, high-grade atrioventricular block, QRS widening and ventricular pre-excitation, and conditional deletion in the adult causes sinus node dysfunction and atrioventricular block [22]. These data are preclinical and explain the search for conduction abnormalities in patients.

The Tbx3-null mouse dies in mid-gestation (between E10.5 and E16.5), with absent induction of the mammary gland and anomalies of the fore- and hindlimbs [4, 14].

Embryology of ulnar deficiency. Ulnar deficiency arises between the 4th and 7th week of gestation. Preaxial/postaxial polarisation of the limb bud depends on the zone of polarising activity (ZPA), on the postaxial border of the bud, which secretes SHH in a gradient decreasing from the 5th to the 2nd ray and determines the identity of rays V to II; experimental removal of the ZPA in avian or mammalian embryos causes the postaxial rays to disappear, and its transplantation to the preaxial border produces a “mirror” extremity [26]. In humans, variants in SHH itself are not known to cause anomalies of the ulna; what is associated with ulnar defects are alterations of regulators and transcription factors of the pathway that controls SHH expression in the limb, among them TBX3 and the HOXD cluster [26, 36]. The extreme form is acheiropodia, in which loss of the action of the ZRS enhancer on SHH leaves only the first ray [26].

2.3. Pathogenic mechanism

Haploinsufficiency is the main mechanism [4, 12]. It is supported by the predominance of truncating variants distributed along the gene, whole-gene deletions [18, 33], the ClinGen haploinsufficiency score of 3 and intolerance to loss of function in gnomAD (pLI 0.99; LOEUF 0.47) [4, 12]. In the Turkish family of Wollnik, an insertion at codon 30 truncating the protein before almost all functional domains produced the typical phenotype [29].

Experimental data suggest additional mechanisms. A mouse allele with deletion of exons 1 to 3 produces a truncated cytoplasmic protein with a phenotype different from that of the true null allele, indicating that not all human variants will be functionally null [37]. Tung and colleagues mention emerging evidence that C-terminal variants exert a dominant-negative effect on the splicing function of the normal allele [9]. In a humanised Drosophila model, missense variants in the T-box reduced protein activity more than variants outside this domain [14]. The mismatch between the ubiquitous expression of TBX3 and the restriction of malformations to a few organs is attributed to partial compensation by TBX2 [4].

2.4. Variant spectrum

The published reviews describe the spectrum with different figures, depending on date and criteria. Galazzi and colleagues gathered 19 pathogenic variants: 16 truncating (11 frameshift and 5 nonsense) distributed throughout the gene and 3 missense clustered in exon 2, in the T-box [13]. Bottillo and colleagues, including ClinVar, counted 28 pathogenic or likely pathogenic variants in 87 postnatal patients; about 54% were truncating up to the penultimate exon and about 25% missense, all in the T-box, mainly in the R2 region, whereas the benign missense variants in ClinVar clustered in the A and R1 domains [14]. Halperin and Weiss add two stop-loss variants in the last exon, which might disrupt phosphorylation sites or generate a longer non-functional protein, and the regional constraint against missense variants around the T-box in gnomAD [4]. Canonical splicing variants [9, 19, 28] and whole-gene deletions [18] have been described.

The variants in the following table were normalised in VariantValidator with the MANE transcript; the original description is retained to allow literature searches [5].

The variants of Bamshad 1997 (deletion of nucleotide 227 and a G>C substitution at the first base of intron 2) and the c.1586_1587insC insertion in exon 6 of Meneghini, which OMIM describes with a frameshift at codon 399 and termination at codon 406, use numbering that does not match the MANE transcript and are cited only in their original form [11, 42].

2.5. Genotype-phenotype correlations

No genotype-phenotype correlation has been established. Bamshad and colleagues found no obvious differences between patients with missense variants and those with deletions or frameshifts [6]. Meneghini and colleagues, combining the data published up to 2006 (56 patients with molecular confirmation in 13 families), associated variants that disrupt the DNA-binding domain with a higher frequency of severe upper limb malformations and dental defects, and proposed that proteins retaining the T-box keep minimal activity [42]. In OMIM, limb defects had a penetrance above 85%; the severe limb phenotype (involvement of the ulna or humerus) was significantly associated with variants that abolish or disrupt the T-box (p = 0.009), whereas the association with mammary (p = 0.092) and dental (p = 0.052) involvement did not reach significance [10]. OMIM also records the absence of an apparent association between the type or severity of the limb defect and the apocrine or genital anomalies [10]. Galazzi and colleagues found no segregation of particular phenotypes between variants before and after the T-box, and 59% of variants were associated with delayed puberty [13]. Variability within the same family, with carriers of the same allele ranging from no signs to severe ulnar deficiency, is the most constant observation [9, 13, 14, 16].

2.6. Penetrance and expressivity

Expressivity is highly variable and often asymmetric [2, 15]. Schinzel described complete penetrance [7], but there are carriers without detectable signs on initial examination: one of the carrier dizygotic twins in the Tung family had a normal hand at three weeks [9], and carrier mothers were considered unaffected until reverse phenotyping [30, 31]. The Oxford Desk Reference mentions variable penetrance [8]. The mammary and apocrine signs are only clearly recognised after puberty, which reduces apparent penetrance in children [14]. The endocrine signs are more penetrant in males [13].

2.7. Structural variants and combined phenotypes

The 1.28 Mb deletion described by Klopocki and colleagues included only TBX3 among the known genes and was associated with a UMS-like phenotype, facial dysmorphism and intellectual disability; the authors attributed the last two features to the involvement of neighbouring genes, without demonstration [18]. Borozdin and colleagues (2006) described a Czech mother and two daughters diagnosed with Holt-Oram syndrome and a contiguous deletion of 2.19 to 2.27 Mb including TBX5, TBX3 and RBM19; re-examination revealed previously unrecognised signs of UMS (breast agenesis, absent axillary hair and reduced sweating in the mother, hypoplastic nipples and areolae in the daughters, hypoplastic hypothenar eminence and a cleft between the fourth and fifth fingers in all) [10]. Contiguous deletions of TBX3 and TBX5 give a combined Holt-Oram and UMS phenotype, with intrafamilial variability and resemblance to Okihiro syndrome [33], and in one patient were associated with symmetrical limb malformations, congenital heart disease and rapidly progressive conduction disease [43]. A tandem duplication of 12q24.21 including both genes segregated in at least 17 individuals over six generations of a German family, with anomalies of the radial and ulnar rays, heart defects, patent ductus arteriosus, aortic stenosis, supernumerary nipples and cardiomyopathy [34]. ClinGen found no evidence of triplosensitivity for TBX3 alone [12].

2.8. Somatic expression in cancer

Somatic overexpression of TBX3 occurs in various carcinomas and sarcomas and is associated with bypass of senescence and apoptosis and with proliferation and invasion [4]. This mechanism, of gain of expression in tumour tissue, is distinct from the germline loss of function of UMS [4].

3. Clinical Spectrum and Manifestations by System

3.1. Data sources and limitations

The clinical data come from case and family reports and three aggregated reviews. Galazzi and colleagues gathered 106 patients with a TBX3 variant (54 men and 52 women) from 17 published families and 2 of their own [13]. Bottillo and colleagues gathered 87 postnatal patients with 28 different variants, 19 (68%) of them in familial cases [14]. Halperin and Weiss reviewed 75 individuals from 25 families and noted that the literature is biased towards the typical presentation and that only recent studies include assessment of gonadotropins, growth hormone (GH) and pituitary imaging [4]. The frequencies below are proportions among published patients, not population estimates, and underestimate the manifestations that were not looked for.

3.2. Upper limb

The defects affect the postaxial (ulnar) elements of the upper limb and are often asymmetric [15, 16]. The spectrum includes hypoplasia of the phalanges of the fifth finger, partial or complete phalangeal fusion of the fifth finger with absent interphalangeal creases, camptodactyly and clinodactyly of the fifth finger, postaxial polydactyly, partial ventral duplication of the nail of the fifth finger, absence of digits 3 to 5 and of metacarpals 3 to 5, aplasia or hypoplasia of the ulna with a short or bowed radius, absence or fusion of carpal bones on the ulnar side, a hypoplastic humerus and, rarely, complete absence of the forearm and hand [4, 14, 15]. A deficiency on one side and a posterior duplication on the other may coexist [16]. Antecubital pterygium with a flexed elbow was described in a female newborn with absence of digits 3 to 5 and of the ulna [44].

The forme fruste, with isolated hypoplasia of the fifth finger or dorsalisation of the little fingers, is frequent in relatives and may be the only manifestation [25, 32]. In the review by Al-Qattan, dorsal dimelia of the ulnar digits, with a nail on the palmar surface of the finger, is one of the defects associated with ulnar ray deficiency [25]. The lower limbs are usually spared; Schinzel described defects of the fibular rays of the feet [7] and Smith mentions short terminal phalanges of the fourth and fifth toes [15], but other authors report no lower limb malformations [44].

3.3. Breast, nipple and apocrine glands

Breast hypoplasia ranges from reduced breast volume to complete absence, with hypoplastic and hypopigmented, inverted, retracted or absent nipples and areolae, sometimes with widely spaced nipples [3, 4, 15]. Lactation may be normal or absent [15, 16]. In Galazzi's family A, the mother's bilateral breast hypoplasia prevented lactation after two pregnancies [13]; in Bottillo's family, the mother underwent augmentation mammoplasty for severe hypoplasia in adulthood [14]. Athelia and nipple hypoplasia are present in both sexes, and in boys may be the most visible sign [3, 13]. Accessory and inverted nipples are occasional findings [15].

Axillary hair and axillary perspiration are reduced or absent, with absence of body odour; in some patients there is a complete inability to sweat, which may affect thermoregulation [4, 15]. In the Bamshad family, apocrine involvement ranged from reduced axillary sweating with normal breasts and lactation to absence of breasts and of axillary sweating [16].

3.4. Hypothalamic-pituitary-gonadal axis

Male genital involvement includes micropenis, unilateral or bilateral cryptorchidism, shawl or bifid scrotum and delayed puberty [4, 15]. In women there is late puberty and menarche, oligomenorrhoea, imperforate hymen and bicornuate uterus [13, 14, 16, 39]. The Oxford Desk Reference mentions reduced fertility in men [8].

The central origin of the hypogonadism was characterised by Galazzi and colleagues in two normosmic probands with delayed puberty, congenital isolated hypogonadotropic hypogonadism (prepubertal response to the gonadotropin-releasing hormone, GnRH, test after the age of 14) and pituitary hypoplasia, without variants in the known genes for hypogonadotropic hypogonadism and hypopituitarism [13]. In one of them, hypogonadism persisted into adulthood: he reached Tanner P5G5 on gonadotropins and again had low testosterone when these were stopped [13]. In two Japanese brothers aged 11 and 7, luteinising hormone (LH) and follicle-stimulating hormone (FSH) responses to GnRH were low to low-normal, with a normal testosterone response to human chorionic gonadotropin (hCG), which the authors interpreted as mild gonadotropin deficiency [39]. One of the Tanteles twins, with low FSH, LH and testosterone and a suboptimal response to GnRH, virilised well on testosterone [10]; Galazzi and colleagues, who report a prepubertal response at 15 years and normal puberty after priming, consider the picture more consistent with constitutional delay [13]. Osman and colleagues described a woman with hypogonadotropic hypogonadism and a hypoplastic pituitary, without limb or breast defects, identified through reverse phenotyping of her twin sons with micropenis and neonatal hypogonadism [31].

3.5. Growth, growth hormone and other pituitary axes

Birth weight is usually normal [4]. Smith describes delayed growth and skeletal maturation, with puberty and catch-up growth often occurring with a delay of 5 to 7 years [15]. Short stature is mild and affects a fraction of patients, with or without GH deficiency [4, 41]. GH deficiency has been documented by stimulation tests: in a girl, peaks of 4.3 ng/mL with clonidine and 2.0 ng/mL on insulin-induced hypoglycaemia [13]; in a 13-year-old boy, a peak of 6.4 ng/mL after clonidine and arginine, with a small adenohypophysis and a Rathke's cleft cyst [3]; and in a boy with adenohypophyseal hypoplasia and an ectopic neurohypophysis [30]. In a Czech cohort of 34 children with combined pituitary hormone deficiency, a boy with a TBX3 variant had GH deficiency (peak 1.8 µg/L), central hypothyroidism and central adrenal insufficiency, with pituitary hypoplasia, an ectopic neurohypophysis, hypoplasia of the corpus callosum, micropenis, cryptorchidism, scrotal hypoplasia and anal atresia [38]. This single case indicates that the pituitary deficiency may extend to the thyrotropic and corticotropic hormones.

All four patients with UMS who had undergone neuroimaging up to 2018 showed some brain or pituitary malformation: pituitary hypoplasia, a thin stalk, an ectopic neurohypophysis, Arnold-Chiari type 1 malformation or descent of the cerebellar tonsils [13].

Obesity has been described in some patients in adolescence or adulthood [7, 13]; Halperin and Weiss consider it infrequent in published cases, although possibly under-recorded [4].

3.6. Face and midline

The dysmorphism is subtle but recognisable: a broad, square or bifid nasal tip, underdeveloped alae nasi, full cheeks with a broad midface, a broad mandible, a pointed and prominent chin and downturned corners of the mouth [4, 15, 41]. Joss and colleagues compared published photographs and proposed that this shared face may raise suspicion of TBX3 in patients with subtle signs [41]. Midline defects include a bilobed tongue, a short lingual frenulum or one reaching the tip of the tongue, a bifid or broad uvula, cleft palate, a high palate and dental anomalies (absent or ectopic canines, dental agenesis, crowding) [4, 13, 15]. Galazzi and colleagues classified the set of nasal, lingual and dental anomalies and the pituitary malformations as midline defects, and consider them the most useful clinical clue in patients with delayed puberty [13].

3.7. Heart

Structural heart defects are occasional: ventricular septal defect with pulmonary stenosis [15, 42], ventricular septal defect with paroxysmal supraventricular tachycardia and a Wolff-Parkinson-White pattern [30], patent ductus arteriosus and mitral valve prolapse [15]. Nguyen and colleagues described a 14-year-old girl with a de novo variant and ventricular pre-excitation via a left accessory pathway and proximal right bundle branch block, studied by electrophysiology [22]. Most series did not assess conduction, so the true frequency of electrocardiographic abnormalities is unknown [22]. Halperin and Weiss consider conduction abnormalities rare in humans [4].

3.8. Other anomalies

The carrier mother of Linden's boy had congenital absence of the left eye, absent axillary hair, reduced sweating, normal breasts and an inverted left nipple, without limb or dental anomalies [10]. Gay and colleagues (1981) described a laryngeal web, ventricular septal defect and short stature in one family, cited by OMIM in the UMS entry [10]. Anal atresia or stenosis, anteriorly placed anus, pyloric stenosis, subglottic stenosis and laryngeal web, renal agenesis or hypoplasia, giant bladder diverticula, scoliosis, inguinal hernia, absent or short xiphoid process and ocular anomalies, including anophthalmia, have been described [4, 7, 13, 15, 31]. Anal atresia appears to be the most common isolated congenital anomaly [4]. Arnold-Chiari type 1 malformation with syringomyelia was described in one proband [13].

3.9. Development and cognition

TBX3 is not associated with developmental delay, and most patients have normal intelligence [4]. Intellectual disability is occasional [15] and was described in the de novo 1.28 Mb deletion, in a 3.5-year-old girl with anal atresia, mesomelic dysplasia of the arms, oligodactyly, hypoplastic nipples, late tooth eruption and moderate intellectual disability, in whom the authors allow for the involvement of neighbouring elements [10, 18].

3.10. Breast and cancer risk

The sources consulted contain no data establishing an increased risk of breast cancer in germline carriers of TBX3 variants. A 2026 case report on unilateral athelia with Paget disease asserts a greatly increased risk in UMS, citing a systematic review that could not be located in Europe PMC and whose digital identifier corresponds, in Crossref, to an encyclopaedia entry unrelated to the syndrome [45]. The known oncogenic role of TBX3 is that of somatic overexpression in tumours [4].

3.11. Natural history and treated disease

Information on natural history is cross-sectional and comes from families. Male pubertal delay is “consistent” in the Bamshad family [16], and Smith describes spontaneous recovery with a delay of 5 to 7 years [15]. The distinction between constitutional delay and permanent hypogonadotropic hypogonadism was made only in patients with hormonal assessment: Galazzi's proband followed up to the age of 18 remained hypogonadal after induction with gonadotropins [13]. The limb deficiency is static; the mammary and apocrine manifestations become evident at puberty [14]. There are no survival studies; in Bottillo's family, the father of the affected woman, with compatible signs never recognised, died at 58 of colon cancer, with no known relationship to the syndrome [14].

3.12. Ulnar deficiency: classifications and functional correlations

Table 3.12a. Bayne classification of ulnar deficiency, with types 0 and V added later

Types 0 and V result from later series: Havenhill and colleagues defined type 0 in 11 patients, with hypoplasia or agenesis of the ulnar rays and of the ulnar side of the carpus, associated anomalies of the radial rays, contralateral ulnar deficiency and syndromic conditions; Goldfarb and colleagues, in 41 patients with “phocomelic” malformations, reinterpreted them as severe proximal longitudinal deficiencies (29 radial, 20 ulnar and 11 combined) and defined type V [26]. Other classifications describe complementary aspects: that of Cole and Manske, in a series of 55 limbs in 45 patients, classifies the thumb and first web space (A normal; B mild involvement, with opposition function; C moderate to severe hypoplasia of the first web space, up to thumb-index syndactyly, malrotation and loss of opposition; D absent thumb) and found anomalies of the thumb or first web space in 73% of hands, accounting for 28 of the 53 recommended operations [46]; that of Ogino and Kato classifies the digits (A hypoplasia; B absence of the 5th ray; C of the 4th and 5th; D of the three ulnar rays; E of all digits), with correlation between the degree of ulnar deficiency, digital severity and elbow anomalies; that of Miller and colleagues (29 patients) guides treatment by hand position (A partial absence of the ulna with a well-positioned hand; B complete absence with a stiff elbow in flexion and pterygium; C humeroradial synostosis in flexion and internal rotation, “hand on flank”; D synostosis in extension, well-positioned hand); and that of Al-Qattan separately describes the shoulder, elbow, ulna, digits, thumb and associated defects [25, 26].

In Al-Qattan's series of 72 patients, types 0 and I were the most frequent ulnar anomalies, absence of the 4th and 5th rays the most frequent hand anomaly and the main indication for surgery, humeroradial synostosis the rarest elbow anomaly, and shoulder instability rare and associated with type V [26]. In a multicentre series of 82 limbs with ulnar deficiency in 62 patients, 55% had femoral, fibular or combined deficiency, and the presence of lower limb deficiency was associated with less severe ulnar deficiency; severity at one level (elbow, ulna, digits, thumb) correlated with that at the others [47]. In 8 unoperated patients, the total active range of motion of the elbow, forearm and wrist was 46% of normal and grip strength 27% of that of the opposite side, with no limitation of bimanual activities; function was worse with humeroradial synostosis or digital anomalies, and the radiographic classification, in the absence of synostosis, correlated poorly with function [48].

4. Clinical Recognition and Warning Signs

4.1. When to suspect, by age and context

In the prenatal period, suspicion arises in the presence of reduction defects of the forearm and hand, especially postaxial and asymmetric; in Bottillo's case, the ultrasound at 15+5 weeks showed severe bilateral defects of the forearms and hands, without other structural anomalies [14]. A family history of minor anomalies of the fifth finger, breast hypoplasia or lack of axillary hair in a parent is the finding that points to TBX3 [14].

In the newborn and infant, the signs are the ulnar defect or postaxial polydactyly, a double or ventral nail on the fifth finger, nipple hypoplasia or athelia, micropenis, cryptorchidism, anal atresia and cleft palate [9, 15, 31, 38]. Bottillo and colleagues recommend looking for genital, mammary, nipple and skin appendage signs in all apparently isolated postaxial anomalies, including in prepubertal children [14]. In the Montreal cohort, none of the three children with a TBX3 variant, all with postaxial polydactyly, had a mammary or apocrine anomaly at 0.6 to 3.8 years, which shows that the absence of these signs in childhood does not exclude the diagnosis [19].

In adolescence, UMS should be considered in a boy with delayed puberty and midline defects (broad or bifid nasal tip, bilobed tongue, lingual frenulum, dental anomalies), absent axillary hair and nipple hypoplasia, even without a limb malformation, and when there are ulnar anomalies in other relatives [2, 13]. In girls, hypoplasia or absence of one or both breasts, late menarche and absent axillary sweating are the usual signs [13, 14].

In children with short stature and GH deficiency or combined pituitary hormone deficiency, especially with pituitary hypoplasia, an ectopic neurohypophysis or micropenis, TBX3 is among the genes to be studied [30, 38, 49]. In adults, suspicion arises in women who cannot breastfeed because of breast hypoplasia and in men with normosmic hypogonadotropic hypogonadism, especially with minor hand anomalies [13, 31].

4.2. Warning signs

4.3. Situations requiring rapid assessment

Situations requiring rapid assessment are palpitations, syncope or tachycardia in carriers, because of the risk of pre-excitation and supraventricular tachycardia [22, 30]; hypoglycaemia, hyponatraemia or haemodynamic instability in a newborn with micropenis or a midline defect, which require central adrenal insufficiency and combined pituitary hormone deficiency, described in one patient with a TBX3 variant, to be excluded [38]; intestinal obstruction or failure to pass meconium due to anal atresia [4]; stridor due to subglottic stenosis or laryngeal web [15]; and hyperthermia in patients with anhidrosis exposed to heat [4].

4.4. Newborn screening

There is no newborn screening for UMS. Detection depends on clinical examination of the newborn and prenatal ultrasound.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal clinical criteria. The diagnosis rests on identification of a pathogenic or likely pathogenic variant in TBX3, or of a deletion including it, in a patient with compatible manifestations [2, 4]. None of the non-molecular investigations is specific; the diagnosis is molecular [2].

5.2. Clinical assessment and investigation of malformations

Radiographs of the upper limbs and hands document the ulnar ray deficiency; examination assesses development of the nipple, breast and apocrine glands, axillary hair, genitalia, teeth and midline structures [2]. Al-Qattan's classification of ulnar ray deficiency separately describes the shoulder, elbow, ulna, digits, thumb and associated defects and is useful for recording severity and planning surgery [25]. Halperin and Weiss propose, for all individuals with a clinical diagnosis or a pathogenic variant, echocardiography, abdominal and gynaecological ultrasound, endocrine assessment and dental assessment [4]. Linden and colleagues and Loyal and Laub recommend brain imaging, GH testing and screening for arrhythmias [30, 44].

In ulnar club hand of any cause, the French PNDS (National Diagnosis and Care Protocol) details the examination at birth: active and passive mobility of all joints of the upper limb, including the shoulder (hypoplasia extending to the shoulder girdle, with stiffness or instability); at the elbow, the range of motion (extension or flexion deficit, or absence of movement), the presence of a pterygium and the strength of the flexors and extensors, which may be absent; at the forearm and wrist, pronation-supination, wrist flexion and extension, posteromedial angulation of the forearm, ulnar deviation and its reducibility, flexibility of the soft tissues of the concavity and excess skin on the convexity, with frequent dorsal contracture; in the hand, agenesis of the ulnar rays and malformations of the remaining radial rays (syndactyly, camptodactyly, symphalangism, delta phalanges), length, opening of the first web space, intrinsic and extrinsic function and the position of the hand in space for bimanual tasks [26]. The contralateral limb is examined for minimal involvement, because a simple ulnar inclination of the wrist, a syndactyly or mild hypoplasia of the 5th finger makes the picture bilateral, and the general examination looks for musculoskeletal anomalies (fibula, mandible, femur, absent patella, scoliosis, clubfoot) [26]. The systematic radiographic work-up includes both forearms in anteroposterior and lateral views with the joints above and below, both hands in anteroposterior view, the upper and lower limbs in anteroposterior and lateral views, the whole spine in anteroposterior and lateral views with the ribs, and the pelvis in anteroposterior view [26].

5.3. Endocrine assessment

Endocrine assessment includes basal and stimulated gonadotropins, sex steroids, GH stimulation tests and pituitary magnetic resonance imaging (MRI) [2, 13]. Galazzi and colleagues used the GnRH test with 100 µg of intravenous gonadorelin and measurement of LH and FSH at 0, 15, 30, 60, 90 and 120 minutes, inhibin B, total testosterone, the odour identification test to exclude anosmia and MRI of the olfactory structures and pituitary [13]. The Endo-ERN guideline lists micropenis, bilateral cryptorchidism, midline defects, hyposmia or anosmia, deafness and renal anomalies as signs favouring congenital hypogonadotropic hypogonadism rather than constitutional delay [20]. Several of these signs belong to the UMS spectrum [13]. The values observed in published patients, including insulin-like growth factor 1 (IGF-1) and anti-Müllerian hormone (AMH), are shown in the table.

The diagnosis of GH deficiency in UMS follows the general rules for paediatric GH deficiency, because there are no syndrome-specific criteria. The 2016 Pediatric Endocrine Society (PES) guideline, with GRADE grading, waives stimulation tests when three conditions coexist: auxological criteria, a hypothalamic-pituitary defect (for example, the congenital malformation with ectopic neurohypophysis and pituitary hypoplasia with an abnormal stalk) and deficiency of at least one other pituitary hormone (conditional recommendation, low evidence); in the newborn with hypoglycaemia, a serum GH below 5 µg/L associated with another pituitary deficiency or with the imaging triad is also sufficient, but a low GH during hypoglycaemia, on its own, is not [50]. Outside these scenarios, the result of stimulation tests should not be the sole criterion (strong recommendation), and the diagnosis requires an insufficient response to two different tests, which can be performed sequentially on the same day [50]. The 10 µg/L threshold, used to separate partial deficiency from normality, has no controlled reference standard: it lies slightly below the mean of children with normal growth, whose 5th percentile is below 5 µg/L in most tests, and in post-marketing registries only peaks below 5 µg/L appreciably improved prediction of response in the first year (specificity of the 10 µg/L threshold estimated at 25%) [50]. Peaks depend on the assay, so the guideline calls for assays harmonised to the IRP IS 98/574 standard, and they are lower in obesity, with no paediatric thresholds corrected for body mass index [50]. In UMS, where delayed puberty is frequent, the recommendation of sex steroid priming before testing in prepubertal boys over 11 years and prepubertal girls over 10 years whose predicted adult height is within −2 standard deviations, so as not to treat constitutional delay of growth and puberty with GH (conditional recommendation), is relevant; the proposed regimen is oral β-estradiol 2 mg (1 mg below 20 kg) on the two nights before the test, or, in boys, 50–100 mg of intramuscular depot testosterone one week before [50]. The guideline advises against measuring spontaneous GH secretion for diagnosis (strong recommendation) [50]. The Czech patient with combined deficiency and the Chinese boy with a peak of 6.4 ng/mL illustrate the two pathways: the first met the three criteria that waive testing (although he was tested), the second, with a small adenohypophysis, was diagnosed by stimulation tests [3, 38].

5.4. Molecular testing

The options are sequencing of TBX3 alone (Sanger), limb anomaly, hypogonadotropic hypogonadism or short stature panels that include TBX3, and exome or genome sequencing [9, 13, 19, 49]. Chromosomal microarray detects 12q24.21 deletions and duplications that include TBX3 and TBX5 [17, 18, 34]. In the Montreal cohort of 132 patients with limb anomalies (2014–2024), the overall diagnostic yield was 36% (48/132): 7 diagnoses by microarray, 30 by panel and 11 by exome (25% of the 43 exomes), and TBX3 was the most frequent gene, with 3 cases [19]. In a cohort of 233 children with GH deficiency treated for at least 5 years and studied with a 398-gene panel, a genetic cause was found in 39 (17%), of which 13 confirmed GH deficiency, one of them in TBX3 [49]. Galazzi and colleagues propose including TBX3 in congenital normosmic hypogonadotropic hypogonadism panels [13].

5.5. Limitations of the tests

A negative result does not exclude the disease. Exon sequencing does not detect deep intronic variants or balanced rearrangements, and deletions of one or more exons require copy number analysis by sequencing or by targeted methods [4, 18]. In Klopocki's patient, TBX3 sequencing and the karyotype were normal and the deletion was found only by array comparative genomic hybridisation [18]. Technical failure is possible in fetal tissues: the exome of the fetal skin tissue in Bottillo's case had insufficient coverage, and the diagnosis was made in the mother [14]. Somatic or germline mosaicism has not been described in the sources consulted, but the possibility cannot be excluded in de novo cases. Variant nomenclature varies between NM_005996 and NM_016569; the report should state the transcript with its version [5, 38].

5.6. Report and variants of uncertain significance

The report should state the gene, the transcript with its version (MANE NM_005996.4), the Human Genome Variation Society (HGVS) notation at c. and p. level, the zygosity, the class according to the rules of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the criteria applied [3, 14, 38]. Published examples: c.1061_1064del (described on NM_016569.3) classified as pathogenic with criteria PVS1 and PS4 [3]; c.400C>T p.(Pro134Ser) as likely pathogenic (PM2, PM1, PP3, PP4) [14]. Missense variants outside the T-box, where the benign missense variants in ClinVar cluster, require caution [14]. In the Montreal cohort, the variant c.804G>C p.(Lys268Asn) was classified as of uncertain significance in two boys with postaxial polydactyly [19]. Segregation studies and reverse phenotyping of relatives (examination of hands, breasts, axillary hair, tongue and nose, and endocrine assessment) contribute to reclassification [4, 14, 31].

5.7. Prenatal and preimplantation diagnosis

The anomaly scan is the main method for limb defects: the limbs are visualised at 13 to 14 weeks and the digits, in general, only at around 20 weeks [8]. Non-invasive prenatal screening for aneuploidies does not detect TBX3 variants; in Bottillo's case, it had been low risk [14]. With the familial variant known, testing on a chorionic villus or amniotic fluid sample and preimplantation genetic testing are possible; severity in the fetus cannot be predicted from the variant, given intrafamilial variability [4, 14].

In France, fetal ulnar club hand is detected mainly at the anomaly scan at 22 weeks of gestation, one of the three recommended scans (one per trimester) [26]. Faced with ulnar deviation of the hand, the PNDS proposes presenting the case at a CPDPN (multidisciplinary prenatal diagnosis centre) meeting (obstetricians, geneticists, radiologists and malformation specialists), completing the assessment with a reference ultrasound and, if the pregnancy is advanced, cross-sectional CT imaging, and offering amniocentesis or chorionic villus sampling if the diagnosis is early, to separate isolated forms (one forearm only) from syndromic forms, with a more guarded prognosis; after disclosure by the CPDPN, it recommends an interval of 10 to 15 days before a multidisciplinary prenatal consultation at an experienced centre (paediatric orthopaedic surgery, physical and rehabilitation medicine, genetics, occupational therapy and psychology), which should be long, separate from routine clinics, free of jargon and, if possible, held around a table and without white coats [26]. In that consultation the parents' history, previous pregnancies, drugs, toxic exposures and bleeding are recorded, the scans are reviewed, the malformation, the aesthetic and functional prognosis, the possible syndromes and the postnatal treatment are described, the contact details of the team and the patient association are given, psychological support is offered and a written report is sent to the parents, the CPDPN and the couple's doctors; when the anomaly already exists in the family, the experience of the affected relative often guides decisions [26]. Microarray is the first genetic test in a fetus with ulnar deficiency, because of the chromosomal regions involved (section 5.9); with the familial TBX3 variant known, targeted testing is applied [4, 26].

5.8. Practical algorithm

5.9. Aetiological investigation of ulnar club hand

Longitudinal ulnar deficiency is less frequent than radial deficiency and, according to the French PNDS, more often syndromic; in the presence of ulnar deficiency, especially bilateral, even if asymmetric, the child should be seen by a geneticist specialising in syndromes, who guides imaging and metabolic and genetic studies according to the examination [26]. The algorithm is as follows [4, 26]:

1. Complete clinical examination and systematic radiographic work-up (section 5.2), with Bayne classification and examination of the contralateral limb.
2. Mammary, apocrine, genital, dental or midline signs, or a family history of postaxial defect → TBX3 sequencing with copy number analysis (ulnar-mammary syndrome).
3. In all cases without an evident diagnosis → chromosomal microarray, because of the alterations described at 12q24 (TBX3), 2q31 (HOXD cluster, whose duplications cause Kantaputra-type mesomelic dysplasia), Xp22.33 and Yp11.2 (SHOX), 4q32-q33 and 6q21 [36].
4. Ulnar deficiency with signs of constitutional bone dysplasia (mesomelic short stature, synostoses, epiphyseal dysplasia) → skeletal dysplasia panel or exome (Table 6.4a).
5. Ulnar deviation of the hand without hypoplasia of the ulna (type 0 with normal forearm) → exclude central neurological, neuromuscular (distal arthrogryposis) or metabolic disease: neurological examination, brain imaging, electromyography, possible muscle biopsy and targeted metabolic studies (Tables 6.4c and 6.4d).
6. Familial isolated ulnar hypoplasia with dominant transmission and no identified cause (MIM 191440) → counselling based on the pedigree.

6. Differential Diagnosis

6.1. Framework

In the classification of the European surveillance network of congenital anomalies (EUROCAT), the defects of UMS are longitudinal defects (absence or severe hypoplasia of the lateral part of the limb, such as ulnar aplasia with absence of the fifth finger), sometimes combined with postaxial duplications [8]. The differential diagnosis is organised along three axes: other ulnar ray and postaxial defects; syndromes with mammary, nipple or apocrine hypoplasia; and genetic causes of hypogonadotropic hypogonadism, GH deficiency and pituitary hypoplasia. Ulnar ray deficiency, of all causes, occurs in 1 in 50,000 to 100,000 live births and is often sporadic [25].

6.2. Comparative table

6.3. Main differential diagnoses

Holt-Oram syndrome is the reference differential for genetic and clinical reasons. TBX5 and TBX3 are T-box genes linked at 12q24.21, but the defects of Holt-Oram are preaxial (radial), bilateral and accompanied by heart disease in 95%, whereas those of UMS are postaxial, often unilateral, and accompanied by mammary, apocrine and genital changes [3, 17, 28]. Loyal and Laub recommend that preaxial malformations should point towards Holt-Oram [44]. When both rays are involved and there is heart disease, microarray is required to exclude a contiguous deletion or duplication of the two genes [33, 34].

The syndromes with nipple hypoplasia and hypohidrosis (Finlay-Marks, ADULT, EEC) share the ectodermal involvement, but the limb defects are digital or central rather than ulnar, and they do not include hypogonadotropic hypogonadism or GH deficiency [3, 8, 58]. The Poland anomaly gives unilateral breast hypoplasia with absence of pectoralis major, which is not part of UMS [8].

The combination of postaxial polydactyly with hypopituitarism or hypogonadism brings UMS close to Pallister-Hall syndrome and Bardet-Biedl syndrome. Pallister-Hall is distinguished by the hypothalamic hamartoma on MRI, the bifid epiglottis and the multiple oral frenula [56]; Bardet-Biedl by the retinal dystrophy present in all patients, early-onset obesity and renal anomalies [57]. In the Montreal cohort, diagnoses of Bardet-Biedl and of UMS both arose in children referred for postaxial polydactyly [19].

In isolated hypogonadotropic hypogonadism, the male:female ratio of delayed puberty is 3 to 5:1, lower than that observed in UMS (7:1), and the frequencies of bilateral cryptorchidism (17.7% in an Italian cohort and 7% in the Pitteloud cohort) and micropenis (2.4% and 8%) are lower than in UMS (22% and 15%) [13]. Orofacial cleft or dental agenesis (31% in UMS versus 9.8%) and renal anomalies (6% versus 0.4%) are also more frequent in UMS than in the Italian cohort of prepubertal-onset hypogonadotropic hypogonadism [13]. The absence of axillary hair and axillary sweating after complete pubertal induction, observed in Galazzi's proband, is a sign that distinguishes UMS from other forms of hypogonadism [13].

6.4. Aetiological diagnosis of ulnar club hand

The following tables bring together the causes of ulnar club hand listed by the French PNDS, with MIM numbers and genes checked in OMIM/MedGen and in the primary literature [26, 61].

Table 6.4a. Constitutional bone dysplasias with ulnar deficiency

Table 6.4b. Multiple malformation syndromes with ulnar deficiency

Table 6.4c. Neurological and neuromuscular causes of ulnar deviation of the hand

Table 6.4d. Metabolic diseases with ulnar deviation of the hands

Sources for the tables: PNDS of the HAS [26]; MIM numbers and genes checked in MedGen (NCBI) [61]; Kantaputra [36]; ulnar agenesis with fibroelastosis [62]. The PNDS writes the MIM number of the femur-fibula-ulna complex as 22820 (the correct number is 228200) and gives Kantaputra-type dysplasia as having an unidentified gene, whereas the cause (duplications of the HOXD locus) was described in 2010.

7. Treatments and Risk Management Strategies

7.1. Principles and organisation of care

There is no scientific society guideline specific to UMS and no gene-directed treatment; management is symptomatic and multidisciplinary [2, 4]. The most recent recommendations are those proposed by the review of Halperin and Weiss, without grading of evidence: care by a team including clinical genetics, orthopaedics, endocrinology and the specialties required; systemic assessment for congenital anomalies with echocardiography, abdominal and gynaecological ultrasound, endocrine and dental assessment in all individuals with a clinical diagnosis or pathogenic variant; treatment of hormone deficiencies with replacement; consideration of fertility preservation protocols; reconstructive breast surgery; avoidance of prolonged heat exposure in patients with anhidrosis; management of obesity with a dietitian and lifestyle change; social, vocational and psychological support; and genetic counselling with segregation studies [4]. Linden and colleagues and Loyal and Laub add brain imaging, GH testing and screening for arrhythmias [30, 44]. The doses of sex steroids, gonadotropins and somatropin used in UMS follow those of the general indications (congenital hypogonadotropic hypogonadism and paediatric GH deficiency), as there are no specific studies; this is an extrapolation, declared as such in each case.

7.2. Upper limb

Limb interventions include splints or physiotherapy for range of motion and motor skills, corrective or reconstructive surgery and prostheses [4]. Loyal and Laub describe splinting or surgery to improve elbow range, reconstruction for digital function and excision of supernumerary digits [44]. Unlike radial deficiency, ulnar deficiency usually has a stable wrist, although a fibrous band replacing the distal ulna may cause ulnar deviation; most operations in ulnar deficiency treat associated defects, such as syndactyly and thumb hypoplasia [25]. In the “hand on flank” deformity with truncation of the contralateral limb, Al-Qattan and colleagues advise against humeral osteotomy to bring the hand forward, because the posterior position allowed the patient to reach the anogenital region, a pocket and the mouth [25]. In the Tung family, the duplicated nail of the fifth finger was surgically excised [9]. The Reach association supports children with upper limb differences in the United Kingdom [8, 63].

For ulnar club hand of any cause, the 2023 French PNDS is the national recommendation available. Management is multidisciplinary, coordinated by paediatric orthopaedic surgery and/or physical and rehabilitation medicine, with genetics, occupational therapy, physiotherapy, psychology, school health and social services; occupational therapy and rehabilitation are intermittent, tied to the timing of surgery and to needs, because a child with unilateral involvement is generally independent [26]. Functional assessment records range of motion, grip strength, bimanual coordination and dexterity, and occupational balance measured by the Canadian Occupational Performance Measure (COPM) helps to weigh the indication for surgery; if surgery involves two sites (for example, humerus and wrist), an occupational therapy assessment is made before each operation [26]. Postural orthoses are used to gain range of motion (elbow, wrist, fingers, wrist realignment), from birth or during growth phases, or to clarify a surgical indication, and only if they reduce the deformity without skin lesions or pain; they are renewed with growth and may be combined with physiotherapy against soft-tissue contractures [26]. Assistive devices, commercial or custom-made, serve daily activities (fork, ruler), sport (bicycle grip, ski pole, canoe paddle), music (violin bow, plectrum) and career guidance [26].

Table 7.2a. Surgery in ulnar club hand according to the French PNDS and the series supporting it

Indications are discussed at a multidisciplinary meeting and explained to the child and family (objectives, expected benefits and risks); aesthetic improvement is generally achieved, but functional improvement is less predictable, because the child adapts well and because the limitations often depend on the hand anomalies [26]. In the type IV series of Elhassan and colleagues (14 patients), surgery was indicated in 6 of 11 unilateral cases and in 2 of 3 bilateral cases, mainly on the hand (6 of 8 indications), with no humeral osteotomy, and limitations in daily and sporting activities were few [26].

7.3. Breast and apocrine glands

Reconstructive surgery may be considered for hypoplasia or absence of the breast or nipple [4]; in Bottillo's family, the mother underwent augmentation mammoplasty in adulthood [14]. The ability to breastfeed cannot be predicted from breast volume: in the Bamshad family, there were women with reduced axillary sweating and normal lactation, and others without breasts or lactation [16]. In patients with anhidrosis, thermoregulation may be impaired, and avoidance of prolonged heat exposure is recommended [4].

7.4. Pubertal induction and sex steroid replacement

The 2022 guideline of the European Reference Network on Rare Endocrine Conditions (Endo-ERN) is the reference for pubertal induction in congenital pituitary or gonadal deficiency [20]. Its systematic review found only four studies in boys with hypogonadotropic hypogonadism and one study with 20 girls, so most recommendations have a low level of evidence (+OOO or ++OO) [20]. Application to UMS is an extrapolation. A multidisciplinary team is recommended [20].

Boys. The guideline recommends specialist assessment if the puberty score is below −2 standard deviations, if there are no signs at 14 years or if progression is inadequate (onset is defined by a testicular volume of at least 4 mL), and pubertal assessment from 9 years in conditions with a risk of hypogonadism [20]. All boys with permanent hypogonadism should undergo induction, which may begin at 12 years if there are no signs of puberty, and testosterone is recommended [20]. Follow-up should be every 3 to 6 months, with assessment of adverse effects (local reaction, gynaecomastia, priapism, haematocrit, liver function and behaviour) [20]. Gynaecomastia occurs in up to one third of patients on gonadotropins or testosterone [20]. Long-acting injectable testosterone undecanoate should not be used to initiate puberty, as it advances bone age [20].

The guideline dose for initiating puberty is lower than that of the FDA label for testosterone enanthate and its escalation slower; the label does not describe gradual progression to the adult dose [20, 65]. In many countries, testosterone formulations are not authorised for pubertal induction [20]. In patients diagnosed late, the guideline allows higher initial doses, of 200–250 mg of enanthate per month and then every 2–3 weeks [20].

Gonadotropins in the boy with hypogonadotropic hypogonadism. The guideline suggests discussing testosterone or gonadotropins with the patient and family (+OOO) [20]. Testosterone does not induce testicular growth or spermatogenesis; the combination of recombinant FSH (rFSH) with hCG is more effective than hCG alone, pretreatment with rFSH before hCG may optimise Sertoli cell maturation, and 6 to 24 months of rFSH with hCG produce testicular growth in almost all patients and spermatogenesis in 80% to 95% of those without cryptorchidism [20]. Published protocols vary; examples cited by the guideline include rFSH 1.5 IU/kg three times a week, rFSH 75–150 IU three times a week (maximum 150 IU) with hCG 250–500 IU twice a week increased every 6 months up to a maximum of 2500 IU three times a week, and FSH 75 IU three times a week with hCG 250–2000 IU twice a week [20]. After induction, switching to testosterone is suggested, with semen analysis and sperm cryopreservation before the change; as 5% to 20% of patients with congenital hypogonadotropic hypogonadism recover axis function, a break of about 4 months before starting testosterone may be considered [20]. In Galazzi's proband, nine months of testosterone enanthate did not make the testes grow (volume −4.9 standard deviations at 16 years and 11 months); this was followed by priming with FSH 75 IU three times a week for 4 months, FSH 150 IU three times a week and hCG from 1000 to 2000 IU twice a week, with increases of 500 IU every 6 months adjusted to testosterone; after 15 months, the testes measured 20–25 mL and the penis 9 cm, and discontinuation at 18 years was followed by low testosterone, fatigue and poor school performance, which improved with transdermal testosterone [13]. The family B proband followed the same protocol at 16.8 years [13]. In a 5.5-year-old Chinese boy with micropenis and hypogonadotropic hypogonadism, 6 months of hCG improved the micropenis [66].

Micropenis in childhood. In two Japanese brothers, two doses of 25 mg of IM testosterone enanthate increased penile length by about 5 mm per dose, a value similar to that of 23 boys with idiopathic micropenis (mean 4.4 mm per dose; range 2.5 to 7.5) [39].

Girls. The guideline recommends specialist assessment if there are no signs of puberty at 13 years, if the puberty score is below −2 standard deviations, or from 8 years if there is an at-risk condition; it recommends starting individualised induction at 11 years if hypogonadism is confirmed, or at 13 if constitutional delay is suspected, with 17β-estradiol and gradual increase over 2 to 3 years to the adult dose [20]. Combined oral contraceptives are not recommended for inducing puberty [20]. A progestogen is added after the first withdrawal bleed or after at least 2 years of estradiol, for 10 days per cycle [20]. Follow-up is every 3 to 6 months (weight, height, blood pressure, Tanner stage, bone age, hormones), with pelvic ultrasound before starting and before the progestogen [20]. Adult estradiol preparations used in adolescents are off-label [20].

7.5. Growth hormone

Somatropin is indicated in proven GH deficiency. There are no specific studies in UMS; the dose is that for paediatric GH deficiency, and the reference is the 2016 PES guideline (declared extrapolation from paediatric GH deficiency in general) [50]. The guideline recommends dosing by weight or body surface area (strong recommendation), with an initial dose of 0.16–0.24 mg/kg/week (22–35 µg/kg/day), subcutaneously 6 to 7 days a week, and subsequent individualisation; some patients need higher doses [50]. Administration three times a week is not suggested, because daily administration gave greater height gain with the same weekly dose [50]. Titration by IGF-1 is not recommended as a dosing method, for lack of adult height data (in a 2-year randomised trial, an IGF-1 target of +2 standard deviations gave more height gain than a target of 0, but required mean doses of 91 versus 37 µg/kg/day); serum IGF-1 serves to monitor adherence and response to dose changes, and the dose should be lowered if IGF-1 exceeds the laboratory's normal range for age or pubertal stage (conditional recommendation, very low evidence) [50]. At puberty, the guideline recommends against routinely increasing the dose to 0.7 mg/kg/week (strong recommendation), and the paediatric dose should not continue after growth velocity falls below 2–2.5 cm/year, with an individual decision for earlier discontinuation (strong recommendation) [50]. The guideline also recommends advance information and clinical surveillance at every visit for intracranial hypertension, slipped capital femoral epiphysis and progression of scoliosis, reassessment of the adrenal and thyroid axes after starting GH when the cause of the deficiency may involve other pituitary axes (with adjustment of hydrocortisone and levothyroxine in those already treated), monitoring of glucose metabolism in patients at risk of diabetes, and information about the uncertainty of long-term risk; it advises against routine echocardiography, densitometry and lipid profile during treatment (conditional recommendation) [50]. The labels serve as a comparison. The Portuguese SmPC of Genotropin® recommends 0.025–0.035 mg/kg/day or 0.7–1.0 mg/m²/day subcutaneously, with rotation of injection sites, and continuation after adolescence until complete somatic development, including peak bone mass with a T-score above −1 [21]; the lower daily limit of the SmPC (25 µg/kg/day) is slightly higher than that of the guideline (22 µg/kg/day), and the SmPC continuation criterion (complete somatic development) differs from the guideline's criterion for stopping the paediatric dose (growth velocity below 2–2.5 cm/year), which refers continuation to the transition reassessment. The FDA label of GENOTROPIN gives 0.16–0.24 mg/kg/week divided into 6 or 7 subcutaneous injections, a range equal to the guideline's initial range [67]; the guideline notes that some products in the USA are approved for up to 0.3 mg/kg/week before puberty and up to 0.7 mg/kg/week during puberty, a dose whose routine use it advises against [50]. The SmPC contraindications include tumour activity, closed epiphyses (for growth promotion) and acute critical illness; the warnings include reduced insulin sensitivity, unmasking of central hypothyroidism, benign intracranial hypertension, slipped capital femoral epiphysis and progression of scoliosis [21]. Long-acting GH is an alternative with fewer injections; the 2025 international consensus notes that long-term and real-world data are still scarce [68].

The results described in UMS are from isolated cases. In Galazzi's family B, the sister with GH deficiency received 0.2 mg/kg/week, 7 days a week, for 6 years from the age of 9.9 [13]. In the patient from the Czech cohort with combined deficiency, height went from −3.9 standard deviations at baseline (3.5 years) to −1.7 after one year and +0.1 after three years [38]. In a Chinese boy, 3.5 years of recombinant GH improved height [66].

7.6. Other pituitary deficiencies

Combined pituitary hormone deficiency, with central hypothyroidism and central adrenal insufficiency, has been described in one patient with a TBX3 variant [38]. The FDA label of testosterone enanthate notes that, in hypogonadotropic hypogonadism, adrenocortical and thyroid replacement, when needed, takes priority [65]. Identified deficiencies are treated according to the usual practice for hypopituitarism; before starting somatropin, thyroid function should be reassessed, as GH may unmask a deficiency [21].

7.7. Cardiac conduction and heart disease

Linden and colleagues recommended screening for arrhythmias in all patients with UMS, after describing a boy with a ventricular septal defect and a Wolff-Parkinson-White pattern [30]; Smith proposes the same screening [15]. Nguyen and colleagues recommend assessing carriers of TBX3 variants for conduction block and ventricular pre-excitation and following them up for the possibility of adult-onset conduction disease, such as sinus node dysfunction and atrioventricular block, a hypothesis based on the mouse model [22]. In the patient they described, the electrophysiological study showed a low-risk accessory pathway (anterograde effective refractory period of 340 ms, retrograde above 400 ms, atrioventricular re-entrant tachycardia not inducible), which was eliminated by radiofrequency ablation with no recurrence after 3 years; the proximal right bundle branch block persisted and 24-hour Holter monitoring at 2 months and 2 years showed normal sinus node function [22]. Risk stratification and treatment of accessory pathways and structural heart disease follow the usual practice of paediatric cardiology. Halperin and Weiss include echocardiography in the initial assessment [4].

7.8. Other malformations and obesity

Anal atresia, cleft palate, pyloric stenosis, subglottic stenosis, renal and bladder anomalies and Chiari malformation are treated according to the usual surgical indications; in Galazzi's proband, decompression of the Chiari type 1 malformation at 15 years improved diuresis [13]. Dental and lingual frenulum anomalies require dental assessment; one proband was operated on at 5 years for a short lingual frenulum [4, 13]. Imperforate hymen, described in women with UMS, should be looked for in girls with pelvic pain or primary amenorrhoea [16]. Obesity is managed with a dietitian and lifestyle intervention [4].

7.9. Drugs and agents to avoid

No drugs specifically contraindicated in UMS have been described. The applicable contraindications and precautions are those of each hormonal treatment: long-acting testosterone should not be used to initiate puberty [20], combined oral contraceptives should not be used to initiate female puberty [20] and somatropin should not be started when there is evidence of tumour activity or closed epiphyses [21].

7.10. Regulatory status

There are no drugs authorised specifically for UMS in any jurisdiction, nor orphan medicinal product designations for this indication in the sources consulted.

7.11. Clinical studies

There are no clinical trials in UMS. The search of ClinicalTrials.gov on 29 October 2026 returned no studies for “ulnar-mammary”; the search for TBX3 returned three studies unrelated to the syndrome (inguinal hernia sacs, HER2-positive breast cancer and stem cell differentiation, the last withdrawn) [69]. Treatment data are limited to case reports and observational cohorts.

These data do not allow comparisons between treatments: they are isolated patients, without a control group, and the response to GH or gonadotropins may reflect the severity of the deficiency rather than the TBX3 aetiology.

7.12. Developments in the last 12 months

In the period up to 29 October 2026, the new data are publications, with no regulatory procedures. The review by Halperin and Weiss (published result, expert opinion) proposed the designation TBX3-related disorder and the first management recommendations directed at the syndrome [4]. The Montreal cohort identified TBX3 as the most frequent gene among limb anomalies with a molecular diagnosis and described children without mammary or apocrine signs [19]. A Czech cohort identified TBX3 among the genetic causes of confirmed GH deficiency [49]. Work in animal and cellular models on T-box factors in the limb and in cardiac conduction remains preclinical.

7.13. Pregnancy and lactation

Women with UMS became pregnant without described fertility treatment in the Galazzi and Bottillo families; in the latter, pregnancy occurred after 2 years of trying [13, 14]. Breast hypoplasia may prevent lactation, as in the mother of Galazzi's family A after two pregnancies [13]; normal lactation with reduced axillary sweating has also been described [16]. Preconception counselling should include the 50% probability of transmission and an anomaly scan focused on the limbs [4, 8]. In women with hypogonadotropic hypogonadism, ovulation induction with gonadotropins is the usual treatment for infertility in adulthood [20].

7.14. Perioperative care and anaesthesia

The subglottic stenosis, laryngeal web, cleft palate and tongue anomalies described in the syndrome should be known to the anaesthetic team before intubation [7, 15]. In patients with hypopituitarism, glucocorticoid replacement under surgical stress depends on the corticotropic axis, whose deficiency has been described in one patient [38]. Anhidrosis requires temperature monitoring [4].

7.15. Transition to adulthood

Hypogonadotropic hypogonadism may persist into adulthood and require continued replacement [2, 13]. The Endo-ERN guideline recommends moving from induction to permanent adult replacement at the end of induction and planned transfer from paediatric to adult endocrinology, and, in the boy treated with gonadotropins, semen analysis and sperm cryopreservation before the switch to testosterone [20]. For GH, the PES guideline considers as persistent deficiency, without the need for retesting, deficiency of three or more pituitary hormones or GH deficiency with a documented causal mutation or with a specific hypothalamic-pituitary structural defect (except isolated ectopic neurohypophysis) (strong recommendation); it recommends reassessing the somatotropic axis in GH deficiency with only one other pituitary deficiency, in idiopathic isolated deficiency and in isolated deficiency with a small pituitary or ectopic neurohypophysis, after at least 1 month off GH, starting with IGF-1 and performing a stimulation test if this is low; and it suggests offering GH at transition to those who remain deficient, although the optimal dose and timing are not defined (conditional recommendation) [50]. The TBX3 variant is a documented genetic cause, but the guideline does not refer to this gene and GH deficiency in UMS has incomplete penetrance; the decision between continuing and reassessing is individual. The Genotropin® SmPC provides for continuation, if the deficiency persists, until complete somatic development [21]. Electrocardiographic surveillance is maintained because of the theoretical possibility of adult-onset conduction disease [22].

In ulnar club hand, the deformity stabilises after adolescence, the young adult has already integrated their limitations and compensations, and surgery is rarely indicated after the end of growth; the adult is followed, if necessary, in an adult rehabilitation or hand surgery service networked with the paediatric centres [26]. For driving, the French PNDS indicates assessment by a doctor accredited by the prefecture before registration, followed by coordination between the occupational therapist and a specialised driving school with adapted vehicles, depending on the side affected and hand function [26].

7.16. Available recommendations and divergences

Table 7.16b. Divergences between the French PNDS on ulnar club hand and other sources

7.17. Psychological support, school and daily life in ulnar club hand

The French PNDS gives the disclosure consultations, prenatal and postnatal, the role of building trust: clear and personalised information, a written document for the parents and the general practitioner on leaving the maternity unit, answers to the usual questions (cause, heredity, other children, offspring, impact on schooling and work, disability, follow-up, treatments with timing, risks and benefits), organisation of the radiographic, aetiological and genetic work-up and scheduling of follow-up, at least every 6 months at first [26]. Psychological support, at the centre or outside it (medico-psychological centres, maternal and child protection services), begins in the prenatal period, aims to reduce the risk of disturbance of the early relationship between parents and baby and may extend until transition, including driving and social integration; the child may refuse orthoses or operations they do not understand, and distress over a visible difference exists even without functional disability [26]. At school, professionals help the teaching team to talk about the malformation and to make adaptations, without imposing an assistant who does for the child what they can do in another way; there is no theoretical contraindication to sport, including at elite level, and it is for the child to gauge their own limits [26].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

UMS is autosomal dominant [12, 15]. Each child of a carrier has a 50% probability of inheriting the variant, regardless of sex; severity in the child cannot be predicted from that of the parent, because expressivity varies greatly within families, from absence of signs to absence of the forearm and hand [9, 14, 16]. Most cases are familial: 19 of the 28 variants (68%) in Bottillo's review and most of the 25 families in the review by Halperin and Weiss; de novo cases are a minority [4, 14]. For the parents of an apparently de novo case with negative testing, the recurrence risk for siblings is low, but not zero, because of the possibility of germline mosaicism, not documented in the sources consulted.

In ulnar club hand without a syndromic diagnosis, the recurrence risk depends on the cause found: isolated ulnar hypoplasia may be sporadic or transmitted in an autosomal dominant manner with no identified gene (MIM 191440), the femur-fibula-ulna complex is sporadic, and the syndromic, skeletal and neuromuscular causes follow the mode of inheritance of the disease (section 6.4) [26]. Examination of the parents, including the hands and wrists, looks for minimal forms before the case is considered sporadic [8, 26].

8.2. Cascade testing and reverse phenotyping

The study of relatives has diagnostic and counselling value. Halperin and Weiss recommend genetic counselling and segregation studies to diagnose other relatives and for prenatal counselling [4]. The Oxford Desk Reference recommends examining the parents' hands and feet for subtle anomalies and considering incomplete penetrance and variable expressivity [8]. In several families, a carrier parent was only recognised as affected after the diagnosis in the child or fetus: Bottillo's mother and grandfather, with minor hand anomalies, breast hypoplasia and sparse axillary hair [14]; Osman's mother, with hypogonadotropic hypogonadism and no limb or breast defects [31]; Linden's mother, without classic features [30]. Assessment of the carrier relative includes the same investigations as for the proband: endocrine, cardiac and ultrasound [4].

8.3. Prenatal and preimplantation diagnosis

With the familial variant identified, molecular testing on chorionic villi or amniotic fluid, or preimplantation genetic testing, can be offered; a positive result does not predict severity [4, 14]. The anomaly scan detects severe defects of the forearm and hand, visible in Bottillo's case at 15+5 weeks, but not mild single-digit forms or the mammary, apocrine or endocrine manifestations [8, 14]. In Bottillo's case, the couple decided to terminate the pregnancy at 17+1 weeks, before the genetic result, and the diagnosis was established afterwards, in the mother [14].

8.4. Fertility

Male fertility may be reduced [8]. In hypogonadotropic hypogonadism, induction with rFSH and hCG allows spermatogenesis in 80% to 95% of patients without cryptorchidism, and discussing sperm cryopreservation is recommended [20]. Halperin and Weiss propose considering fertility preservation protocols [4]. There are affected men with affected offspring, such as the grandfather in family A and the father in family B of Galazzi and the father in the Tung family [9, 13].

8.5. Minors

Testing of at-risk children has direct clinical benefit, because GH and gonadotropin deficiencies, conduction abnormalities and renal and anal anomalies benefit from detection [4, 22]. Carrier children without signs should have pubertal assessment from 9 years (boys) or 8 years (girls), in line with the Endo-ERN guideline for conditions with a risk of hypogonadism [20]. Information given to the child should be progressive and age-appropriate, with psychological support during puberty [4, 20].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence

The prevalence of UMS is unknown; Orphanet assigns it the class “unknown” and records about 128 cases or families published worldwide, a figure also used by Zhang and colleagues and by Tung and colleagues [1, 3, 9]. Smith mentions more than 80 patients [15] and Loyal and Laub, in 2014, about 117 [44]. These figures count published patients and do not measure frequency in the population. The broad expressivity, the forms without limb or breast involvement and the late recognition of relatives indicate underdiagnosis [2, 4, 14]. Ulnar ray deficiency, of all causes, occurs in 1 in 50,000 to 100,000 live births [25]. In the Montreal limb anomaly cohort, TBX3 accounted for 3 of the 48 molecular diagnoses (about 6%) [19].

Longitudinal ulnar deficiency of all causes has an incidence estimated by the French PNDS at 1/100,000 live births and by Al-Qattan and colleagues at 1/50,000 to 1/100,000; neither estimate comes from a population-based registry [25, 26].

9.2. Geographical distribution

The published families come from several populations: the United States (Utah, with 33 affected individuals over six generations, and Iowa) [9, 16], Switzerland [7], Turkey [29], Japan [39], France [42], the United Kingdom [30, 41], Italy [13, 14], Cyprus [40], Saudi Arabia [32], China [3, 66], Israel [31], the Czech Republic [38], Germany [18] and Canada (Quebec, three French-Canadian children) [19]. Up to 2023, two cases had been described in China [3]. Each family has its own variant and no founder variants have been described [13]; the same variant of uncertain significance in two French-Canadian boys was not studied for a common origin [19]. The sources consulted include no data from Portugal or Brazil.

9.3. Special populations

The endocrine manifestations are more penetrant in males, and delayed puberty has a male:female ratio of 7:1 [13]. In girls, breast hypoplasia is often the first sign recognised, at puberty [14]. In young children, the absence of mammary and apocrine signs is usual and does not exclude the diagnosis [19]. In adults, UMS may present as persistent normosmic hypogonadotropic hypogonadism [13, 31].

9.4. Reference networks and patient associations

ERN ITHACA (European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability) covers rare congenital malformations, and Endo-ERN (European Reference Network on Rare Endocrine Conditions) covers hypogonadism and hypopituitarism [23, 24]. In the United Kingdom, the Reach association supports children with upper limb differences [8, 63]. Orphanet maintains the entry ORPHA:3138 [1].

In France, ulnar club hand is followed at the reference centres for developmental anomalies and malformation syndromes: the 2023 PNDS was promoted by the Île-de-France centre (coordinated at the Robert-Debré Hospital), with the associated sites of the Armand-Trousseau Hospital and the Saint-Maurice Hospitals (CEREFAM) [26]. Care may be recognised as an off-list long-term condition, with exemption from patient co-payment, and social services support applications to the MDPH (departmental disability office), child social welfare and funding for equipment; the ASSEDEA association supports families of children with limb malformations, with information at every stage (school, social life, driving licence, treatments) [26].

10. Illustrative Clinical Case

10.1. Family A of Galazzi and colleagues (Italy, 2018)

A 14-year-old boy was referred to an Italian academic centre for endocrine assessment because of delayed puberty, micropenis (stretched length 3 cm), dyslipidaemia and obesity (body mass index of 31.2 kg/m², above the 95th percentile) [13]. He had previously undergone brain and spinal MRI for urinary incontinence, which had shown syringomyelia, pituitary hypoplasia, a thin pituitary stalk flattened against the posterior wall of the sella turcica and dysmorphism of the skull base with horizontalisation of the clivus, consistent with Arnold-Chiari type 1 malformation; abdominal MRI showed right renal hypoplasia and cranial imaging a crowded upper right dental arch [13]. Examination showed an inverted right nipple and a hypoplastic left nipple; the wrist radiograph was normal [13].

The other pituitary functions were normal (insulin-like growth factor 1 of 201 ng/mL, thyroid-stimulating hormone of 1.85 mU/L, free thyroxine of 15.9 pmol/L, prolactin of 6.1 ng/mL), but the GnRH test gave a prepubertal response (LH from 0.1 to 0.4 IU/L and FSH from 0.7 to 2.9 IU/L), with inhibin B of 70 pg/mL and testosterone of 0.05 nmol/L [13]. The patient was normosmic on the odour identification test and the olfactory structures were normal on MRI; the karyotype was 46,XY [13]. At 15 years he underwent surgical decompression of the Chiari malformation, with improvement in diuresis [13].

The family history guided the diagnosis. The mother had had menarche at 14 years, absence of the fourth and fifth fingers of the left hand with ipsilateral ulnar hypoplasia, asymmetric ulnar deformity, bilateral breast hypoplasia more marked on the left that prevented lactation after two pregnancies, a bilobed tongue, a broad nasal tip, asymmetric palpebral fissures and almost absent axillary hair without axillary perspiration; the maternal grandfather had had his pubertal growth spurt at 17 years, clinodactyly of the right fifth finger, camptodactyly of the left fourth finger and hypoplasia of the distal phalanx of the left fifth finger [13]. A hypogonadotropic hypogonadism and hypopituitarism gene panel was negative, and TBX3 sequencing showed in the proband, mother and grandfather the heterozygous variant c.857_858del, p.(Thr286ArgfsTer20) on the MANE transcript NM_005996.4, described in the article as c.857-858delCT, p.T286RfsX19, in exon 4, with premature termination [5, 13]. The other relatives studied did not carry the variant [13].

The proband received testosterone enanthate for 9 months, without testicular growth (volume −4.9 standard deviations at 16 years and 11 months) [13]. He then started priming with FSH 75 IU three times a week for 4 months, followed by FSH 150 IU three times a week and hCG from 1000 to 2000 IU twice a week, with increases of 500 IU every 6 months adjusted to testosterone levels [13]. Testosterone and inhibin B rose progressively; after 15 months, the testes measured 20–25 mL and the stretched penile length was 9 cm [13]. At 18 years, at Tanner stage P5G5A1, gonadotropins were stopped; testosterone fell again (7.5 nmol/L) and fatigue and poor school performance appeared, which improved with transdermal testosterone [13]. The absence of axillary hair and axillary perspiration persisted after complete pubertal induction [13]. The authors considered him the first adult with UMS meeting the classic clinical and biochemical criteria for congenital normosmic hypogonadotropic hypogonadism [13].

The figures of the article show the proband's nipples at 14 years, the wrist radiograph, the phenotype at 14 and 18 years and the mother's hand, breasts and tongue (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC6300862/figure/fig2/), the MRI images of the pituitary, the Chiari malformation and the kidneys (Figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC6300862/figure/fig3/) and the frequencies of manifestations in 106 published patients (Figure 4: https://pmc.ncbi.nlm.nih.gov/articles/PMC6300862/figure/fig4/) [13].

10.2. Interpretation of the case

The case brings together the elements leading to diagnosis in adolescence: delayed puberty with micropenis, midline defects (pituitary, teeth, tongue in the mother), apocrine involvement and ulnar anomalies only in the relatives. Induction with gonadotropins after testosterone is consistent with the Endo-ERN guideline, which accepts both options in the boy with hypogonadotropic hypogonadism and prefers rFSH priming when testicular growth and spermatogenesis are sought [20]. Stopping gonadotropins at 18 years without a planned switch to testosterone differs from the guideline recommendation, which suggests switching to testosterone after induction, possibly after a break of about 4 months to assess recovery of the axis [20]; in this patient, the break confirmed persistence of hypogonadism [13].

10.3. Complementary case: prenatal diagnosis

Bottillo and colleagues described a 33-year-old woman whose first pregnancy showed, at 15+5 weeks, severe reduction defects of the forearms and hands; the fetus had absence of the left hand, two ossified digits on the right, a single long bone in each forearm and anal stenosis [14]. The mother, considered healthy, had mild hypoplasia of the left fifth finger with radiological anomalies of the ulnar carpal bones and metacarpals, an operated imperforate anus, augmentation mammoplasty for severe hypoplasia, reduced perspiration and body odour, sparse axillary hair and menarche at 15 years; her father had hypoplasia of the fifth finger, sparse axillary hair and nipple hypoplasia [14]. The variant c.400C>T p.(Pro134Ser) in the T-box was identified in the mother and the fetus (Figure 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC11649972/figure/jcp31440-fig-0001/) [14]. The case shows how a mild form can go unnoticed until the birth of a severely affected offspring.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Intelligence is generally normal and there is no established association with developmental delay [4]. Functional prognosis depends on the severity of the limb defect, which is static [25]. Growth and puberty are often delayed; Smith describes recovery with a delay of 5 to 7 years [15], but patients with hormonal assessment showed persistent hypogonadotropic hypogonadism in adulthood, requiring continued replacement [13]. The response to GH was favourable in the patients with proven deficiency described [38, 66]. The risk of arrhythmia has not been quantified; the only patient studied by electrophysiology had a low-risk accessory pathway [22]. There are no specific data on life expectancy or quality of life. There are no data establishing an increased risk of breast cancer in germline carriers [4].

In ulnar club hand, children have a great capacity for adaptation and integration; function depends mainly on the elbow, humeroradial synostosis and the hand, more than on the radiographic type, and the deformity stabilises after adolescence [26, 48].

11.2. Surveillance table

The following intervals derive from the recommendations of the review by Halperin and Weiss, the recommendations of case reports and the Endo-ERN guideline for pubertal induction, and from somatropin practice; there is no validated surveillance protocol for UMS.

12. Summary and Final Considerations

Ulnar-mammary syndrome is an autosomal dominant disorder caused by haploinsufficiency of TBX3, a T-box transcription factor that organises the posterior boundary of the upper limb, induces the mammary gland and takes part in the development of the pituitary, hypothalamus, teeth, genitalia and cardiac conduction system [4, 13, 28]. The gene-disease relationship is definitive and haploinsufficiency is well established [12].

The classic picture combines postaxial upper limb defects, mammary and nipple hypoplasia, absent axillary hair and perspiration, micropenis, cryptorchidism and delayed puberty [15, 16]. Studies with hormonal assessment and imaging have shown that the hypogonadism is central, associated with pituitary hypoplasia, may persist into adulthood and is sometimes accompanied by GH deficiency and, in one patient, by combined pituitary hormone deficiency [13, 38]. Expressivity varies within families, from absence of signs to absence of the forearm, and there are forms without limb or breast defects, recognised through hypogonadism, midline defects or bladder anomalies [9, 14, 31].

The diagnosis is molecular and should be sought in an apparently isolated postaxial defect, especially with mammary, apocrine or genital signs, in a boy with delayed puberty and midline defects and in a child with GH deficiency and pituitary hypoplasia [13, 14, 49]. Examination of the parents and reverse phenotyping identify affected relatives. Contiguous deletions of TBX3 and TBX5 require microarray and give a phenotype combined with Holt-Oram syndrome [33, 34].

Management is multidisciplinary: limb surgery and rehabilitation, pubertal induction according to the Endo-ERN guideline, somatropin in proven GH deficiency, cardiac assessment with echocardiography and electrocardiography, abdominal and gynaecological ultrasound, dental care and genetic counselling [4, 20, 22]. There are no clinical trials and no gene-directed therapy; prevalence is unknown and the evidence on treatment and prognosis comes from case reports.

In ulnar club hand of any cause, the PNDS of the HAS (2023) calls for systematic genetic assessment, especially in bilateral forms, microarray and investigation for bone dysplasias, syndromes, neuromuscular and metabolic diseases, orthoses and occupational therapy according to needs, surgery discussed case by case (early resection of the ulnar anlage, hand surgery, humeral and radial osteotomies, one-bone forearm in type II) and follow-up every 6 to 12 months until the end of growth [26].

13. References

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