The portal for rare diseases and orphan drugs

Up to date, approximately 128 cases of Ulnar-mammary syndrome (UMS) have been reported in the literature.

Upper limb defects are the most common presenting feature of UMS at birth. Whilst the upper limbs can be normal, the limb phenotype is variable and can range from hypoplasia of the distal phalanges of the fifth finger(s), camptodactyly and/or postaxial polydactyly to absent ulnar ray digits, absent or hypoplastic ulna and a reduced humerus at the severe end of the spectrum. Abnormalities may be bilateral but are frequently asymmetric; lower limb defects have not been reported. The variable mammary and apocrine features of UMS may not be apparent until puberty and include mammary gland tissue hypoplasia (leading to absence of breast development and the inability to lactate), areolar or nipple hypoplasia, inverted nipples and apocrine gland hypoplasia (that can result in diminished perspiration and body odor). Absent or reduced axillary hair has also been described. Shared facial features of UMS include a wide face tapering to a prominent chin, a broad nasal tip, a wide nasal base, and a bifid tongue tip. Genital defects can include micropenis, shawl scrotum, cryptorchidism, septate uterus, and imperforate hymen. Delayed puberty is noted, particularly in males (79%), due to hypogonadism. Obesity and short stature are also common in individuals with UMS and a pituitary endocrine deficiency (growth hormone, pituitary hypoplasia) has been suggested as a possible cause. Abnormalities of the teeth with ectopic, hypoplastic or absent canines have been noted in a number of individuals. Cardiac defects (ventricular septal defects or conduction abnormalities), renal and anal anomalies (imperforation, anteposition) have been reported in a few cases.

UMS is caused by loss-of-function variants in the TBX3 gene (12q24.21). A hotspot of missense variants is observed in the DNA-binding domain of the TBX3 protein. TBX3 is a member of the T-box gene family. These genes encode transcription factors that have been shown to be important in embryologic development and in the morphogenesis of multiple organ systems.

Diagnosis of UMS is based on clinical findings and family history. It can be confirmed by molecular genetic analyses of TBX3.

Differential diagnoses include limb-mammary syndrome (due to TP63 variants) and Poland syndrome (which is sporadic).

Prenatal testing is based on DNA analysis of amniocentesis and chorionic villus sampling and may be useful to confirm ultrasound and echocardiography findings in families with a known Ulnar Mammary syndrome mutation.

UMS is an autosomal dominant condition commonly reported in families. There is an important inter- and intra-familial variability in expression; however, there is no obvious phenotypic difference between those who have missense variants and those who have frameshift or stop-gain variants. Genetic counseling is possible for affected individuals, informing them that there is a 50% risk of having an affected child at each pregnancy.

Management is multidisciplinary and includes geneticists, orthopedic surgeons and pediatric orthopedics, endocrinologists, cardiologists, as well as social support networks.

Prognosis is variable. Functional impact in everyday life is based on the type and severity of upper-limb anomalies and of endocrinologic anomalies (short stature, infertility, etc.). Life expectancy is the same as in the general population.