Ulnar-Mammary Syndrome

A number sign (#) is used with this entry because of evidence that ulnar-mammary syndrome (UMS) is caused by heterozygous mutation in the TBX3 gene (601621) on chromosome 12q24.

Description

The ulnar-mammary syndrome is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies (Bamshad et al., 1996).

Clinical Features

Schinzel (1973) studied a Swiss kindred in which the proband, brother, father, and nephew had ulnar ray defects, small penis, delayed puberty, and obesity; the proband and his father also had anal atresia. The hand malformation varied from hypoplasia of the terminal phalanx of a stiff fifth finger to complete absence of fingers 4 and 5, including their metacarpals. The proband also had pyloric stenosis. The father had congenital laryngeal stenosis from a subglottic cartilaginous web. Temtamy and McKusick (1978) included information on the family studied by Schinzel (1973) in their compendium of inherited hand malformations and designated the disorder Schinzel syndrome.

Pallister et al. (1976) reported a complex malformation syndrome in a young woman showing abnormal development of ulnar rays, breasts, axillary apocrine glands, teeth, palate, vertebral column, and urogenital system. Eight members of 3 generations were affected. Most of those affected were female.

Gonzalez et al. (1976) reported affected mother and son with ulnar-mammary syndrome of Pallister. The mother had absence of body odor and axillary sweating, and absence of breast tissue with hypoplasia of the nipples and areolas. She also showed absence of one kidney. The son likewise had no axillary sweating. Both the mother and the son had postaxial polydactyly of one hand, and the son had also unilateral oligodactyly with absent ulna and hypoplasia of the ipsilateral shoulder girdle.

Schinzel et al. (1987) gave a full report of their original family (Schinzel, 1973), which contained 4 affected males in 3 successive generations. They defined the major features as the following: ulnar finger and fibular toe ray defects; delayed growth and onset of puberty, obesity, hypogenitalism and diminished sexual activity; and hypoplasia of nipples and apocrine glands with subsequent diminished ability to perspire. Additional findings in single cases included pyloric, anal, and subglottic stenosis. At the time of the report, an additional 12 patients in 3 families had been described, including the family reported by Gonzalez et al. (1976). Schinzel (1987) provided a review.

Hecht and Scott (1984) described the disorder in mother and daughter. The daughter had pyloric stenosis requiring surgical correction and bilateral inguinal hernias were repaired at 6 months. The daughter had complete absence of the right 3rd, 4th, and 5th ulnar rays, absent right ulna with short and bowed right radius and dimple at the elbow. The left hand lacked the 5th ulnar ray and was otherwise normal. The mother had bilateral short, stiff 5th fingers with absent flexion creases and with hypoplasia of the ulnar side of both hands.

Gay et al. (1981) described a family in which congenital laryngeal web occurred in a 23-year-old woman, 2 of her brothers, and their mother. All except 1 brother were short of stature and had associated ventricular septal defect. The mother, born in Yemen, was related to her husband.

Franceschini et al. (1992) described a 3-generation family in which 4 individuals had variable manifestations of the ulnar-mammary syndrome, including ulnar ray defects, obesity, hypogenitalism, delayed puberty, hypoplasia of nipples and apocrine glands, and a previously undescribed ectopia of upper canines. The index patient also had split hand on the right due to complete absence of the fourth ray. They suggested that this finding supported the hypothesis of Lenz (1980) that the split hand with aplasia of the ulna syndrome is the same entity as the ulnar-mammary syndrome.

Apocrine abnormalities in UMS range from normal breast development and lactation with minimally diminished axillary hair and perspiration to complete absence of breasts, axillary hair, and perspiration (Bamshad et al., 1997). Dental abnormalities include ectopic, hypoplastic, and absent canine teeth. Males consistently experience delayed pubertal development. Genital anomalies, such as micropenis, shawl scrotum, and imperforate hymen have been observed in some affected individuals. No association between the type or severity of limb involvement and apocrine or genital anomalies is apparent. Postaxial limb defects range from hypoplasia of the terminal phalanx of the fifth digit to complete absence of the forearm and hand. Duplication of posterior structures with or without contralateral limb deficiencies also occur; in some individuals, partial duplication of the nail on the ventral surface of the fifth digit was found.

Sasaki et al. (2002) performed endocrine studies on 2 brothers, aged 11 and 7, with ulnar-mammary syndrome. GnRH stimulation tests indicated low to low-normal gonadotropin (152760) responses, and hCG stimulation tests showed normal testosterone responses. Administration of testosterone enanthate was effective, with the brothers attaining penile length increases similar to those of treated, age-matched boys with idiopathic micropenis. Sasaki et al. (2002) suggested that mild gonadotropin deficiency may be the primary cause for abnormal external genitalia in UMS.

Linden et al. (2009) reported a 5-year-old boy who was born with bilateral symmetric upper limb anomalies, including bilateral absent ulnae with missing fourth and fifth fingers, bilateral curved radii, camptodactyly of the index and middle fingers, hypermobile thumbs, and fixed flexion of the elbows. No abnormalities were noted in his lower limbs. He also had inverted nipples. Echocardiography shortly after birth revealed a small perimembranous ventricular septal defect, which subsequently closed spontaneously. He had a perinatal episode of supraventricular tachycardia, and electrocardiography was consistent with Wolff-Parkinson-White syndrome (WPW; see 194200). Left cryptorchidism was treated with orchidopexy at 3 years of age. At 5 years of age, short stature became apparent, and he was found to have growth hormone deficiency. Brain MRI revealed a hypoplastic anterior pituitary with a thin stalk and an ectopic posterior pituitary gland. His mother had absent axillary hair, reduced sweating, normal breasts, but an inverted nipple on the left side. She was born with an absent left eye. She had hyperthyroidism, as did her mother and maternal grandmother, but none of them had endocrine testing. She had normal teeth and limbs, and radiographs of her hands and arms as well as an echocardiogram were normal.

Tanteles et al. (2017) reported a Cypriot family in which teenaged twin brothers and their father had variable manifestations of UMS. Twin 1 had a round face, mild hypertelorism, medially flared eyebrows, upslanting palpebral fissures, beaked nose with broad nasal base and bifid tip, simple left ear, hypoplastic underpigmented nipples, absence of the right 5th and left 4th and 5th digits, marked camptodactyly of the 3rd digit, and a bifid scrotum. Twin 2 had flared eyebrows, left-sided postaxial polydactyly of the hand and foot, flared eyebrows, blepharoptosis, long uvula, hairy elbows, and absence of the 4th and 5th digits of the right hand. Twin 2 also had low levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone, as well as suboptimal response of FSH and LH after GnRH stimulation; he virilized well with testosterone treatment. The father had a hypoplastic left 5th finger terminal phalanx with right 5th finger camptodactlyly and absent distal flexion crease.

Mapping

In a large Utah family with ulnar-mammary syndrome, Bamshad et al. (1995) identified 33 affected individuals, a number greater than the sum of all previously reported cases at that time. By linkage analysis they demonstrated that the UMS locus is situated in a 21-cM region on 12q. This region overlaps that in which a locus for Holt-Oram syndrome (142900) had been mapped, suggesting that these disorders may be allelic or caused by mutations in different genes within a closely linked cluster of genes affecting limb development. The UMS gene was mapped specifically to 12q23-q24.1. Linkage analysis demonstrated a lod score of 6.21 at theta = 0.00 with the marker D12S79 and recombinants bracketed the UMS gene to the 21-cM region. Bamshad et al. (1997) reported that subsequently a common ancestor was identified linking the large Utah kindred (family L) with the kindred reported by Pallister et al. (1976).

Cytogenetics

Borozdin et al. (2006) reported a Czech mother and 2 daughters who were diagnosed with Holt-Oram syndrome, in whom they identified a 2.19 to 2.27-Mb contiguous deletion encompassing the TBX5 and TBX3 genes. Clinical reexamination confirmed the presence of features of ulnar-mammary syndrome that were previously unrecognized, including agenesis of the mammary glands, absence of axillary hair, and reduced axillary perspiration in the mother, and hypoplastic nipples and areolae in the daughters, and hypoplastic hypothenar eminences and clefts between the 4th and 5th fingers in all. Borozdin et al. (2006) noted that the contiguous deletion also included the RBM19 gene (616444), but commented that it was unlikely to contribute to or modify the phenotype since all the anomalies present in the affected individuals could be explained by either TBX5 or TBX3 haploinsufficiency.

Klopocki et al. (2006) described a 3.5-year-old girl with an ulnar-mammary-like phenotype, dysmorphic facies, and mental retardation. The patient had anal atresia noted at birth as well as severe bilateral upper limb abnormalities, with mesomelic dysplasia of both arms and oligodactyly with hypoplastic fingers. Other dysmorphic features included capillary nevus flammeus on the central forehead, large eyebrows, flat nose, big mouth, small lips, short neck, slight pectus carinatum, bilateral hypoplastic nipples, and delayed tooth eruption. She also had moderate mental retardation. Sequencing did not detect a mutation of the TBX3 gene, but microarray CGH revealed heterozygosity for an interstitial 1.28-Mb deletion on chromosome 12q24.21, encompassing the TBX3 gene. Neither parent carried the deletion. Klopocki et al. (2006) stated that this was the first description of TBX3 haploinsufficiency caused by a genomic deletion in a patient with ulnar-mammary syndrome, and suggested that the facial changes and mental retardation observed in this patient might be due to involvement of neighboring genes.

Molecular Genetics

Bamshad et al. (1997) demonstrated that mutations in the TBX3 gene are responsible for UMS. In 1 family, they demonstrated heterozygosity for a 1-bp deletion that caused a frameshift and premature termination of the TBX3 gene product (601621.0001). In a second family, they identified a splice donor site mutation (601621.0002). Both were predicted to perturb DNA binding. They did not succeed in demonstrating a mutation in the large Utah kindred. Mutations in the closely linked and structurally related TBX5 gene (601620) cause anterior limb abnormalities in Holt-Oram syndrome (142900), in association with cardiac anomalies. Bamshad et al. (1997) suggested that during the evolution of TBX3 and TBX5 from a common ancestral gene each acquired specific yet complementary roles in patterning the mammalian upper limb. Mutations in TBX5 cause anterior (preaxial) limb anomalies; those in TBX3 cause posterior (ulnar or postaxial) limb changes.

In a Japanese mother and her 2 sons with ulnar-mammary syndrome, Sasaki et al. (2002) identified heterozygosity for a nonsense mutation in the TBX3 gene (K273X; 601621.0003).

In affected members of a large 3-generation Turkish family segregating autosomal dominant ulnar-mammary syndrome, Wollnik et al. (2002) identified heterozygosity for a frameshift mutation in TBX3 (601621.0004). The authors noted that phenotypic expression was highly variable among affected family members.

In a boy and his mother with ulnar-mammary syndrome, Linden et al. (2009) identified heterozygosity for a nonsense mutation in the TBX3 gene (Q331X; 601621.0005). The boy displayed pituitary and cardiac anomalies not previously reported in UMS. Linden et al. (2009) noted that TBX3 is expressed in both the developing heart and the pituitary gland, and suggested that these anomalies might represent an expansion of the UMS phenotype.

In twin brothers and their father with ulnar-mammary syndrome, Tanteles et al. (2017) identified heterozygosity for a nonsense mutation in the TBX3 gene (Q475X; 601621.0006). The twins showed classic features of the disorder, whereas their father was mildly affected.