Catel-Manzke Syndrome

A number sign (#) is used with this entry because of evidence that Catel-Manzke syndrome (CATMANS) is caused by homozygous or compound heterozygous mutation in the TGDS gene (616146) on chromosome 13q32.

Description

Catel-Manzke syndrome is characterized by the Pierre Robin anomaly, which comprises cleft palate, glossoptosis, and micrognathia, and a unique form of bilateral hyperphalangy in which there is an accessory bone inserted between the second metacarpal and its corresponding proximal phalanx, resulting in radial deviation of the index finger (summary by Manzke et al., 2008).

Clinical Features

Catel (1961) reported a 6-week-old male infant with clefting of the hard palate, glossoptosis, and micrognathia (Pierre Robin anomaly), who also had an accessory ossification center at the base of the proximal phalanx of the index finger, causing bilateral clinodactyly. Manzke (1966) reexamined the same patient at 6.5 years of age, and pointed out the supernumerary ossification center as a distinct form of hyperphalangism, which did not fit any classification. Manzke et al. (2008) reported follow-up of the original patient, who was reexamined at age 27 and 47 years. He was not substantially disabled and managed his own business. Growth of his mandible had achieved an almost normal profile, and speech was hypernasal due to a small defect remaining in his hard palate. The mobility of his index fingers was reduced, but he could grasp objects with the thumb and forefinger. There were increasing contractures of the little fingers. Radiographs showed that the accessory bone had been totally fused with the proximal phalanx on the right hand. There was also an atypical cone-shaped splinter of a bone on the ulnar side of the metacarpophalangeal joint. In the left hand, which had surgical intervention, the accessory bone had fused with the proximal phalanx and the metacarpal bone of the forefinger.

Stevenson et al. (1980) reported a male infant proband with features of the Catel-Manzke syndrome as well as short distal phalanges of the index fingers and flexed fingers 2 to 4. The family had multiple affected members including the maternal grandfather who had an identical malformation of the right index finger, the left index finger having only the radial deviation at the metacarpophalangeal joint. The maternal great aunt and a maternal uncle were said to have had the same hand anomaly as the proband. They authors noted that their proband was the sixth reported case in the literature.

Sundaram et al. (1982) reported the presumed eighth case of the combination of micrognathia, glossoptosis and cleft palate, representing the Pierre Robin sequence, with anomaly of both index fingers (accessory ossicle at the base with resulting ulnar deviation).

Dignan et al. (1986) reported the first female patients with Catel-Manzke syndrome: 2 sisters. The proband had hypertelorism, full cheeks, posteriorly rotated ears, Pierre Robin anomaly, and bilateral anomaly of the index fingers in the form of an extra bone between the second metacarpal and its proximal phalanx. A subsequent pregnancy resulted in delivery at 26 weeks of a stillborn female fetus with cleft palate, index finger anomalies, and congenital heart malformation.

Thompson et al. (1986) described a case. They referred to the digital anomaly as bilateral duplication of the proximal phalanges of the index fingers. Their patient had a 'new' feature: dislocatable knees.

Wilson et al. (1993) reported a possible case in a boy with short stature, developmental delay, right iris coloboma, small palpebral fissures, micrognathia, and skeletal anomalies including striking hyperphalangy of the index fingers, bilateral fifth finger clinodactyly, short halluces, and scoliosis. Internal anomalies included asymmetric and dilated cerebral ventricles and ventricular septal defect. Two maternal uncles of the mother had died at ages 13 months and 5 years, respectively, with similar anomalies.

Petit et al. (1994) gave the diagnosis of Catel-Manzke syndrome to the case of a female fetus with the combination of Pierre Robin anomaly, nuchal edema, bilateral radial defects, multiple hand malformations including bilateral hyperphalangy and brachymesophalangy, costovertebral anomalies, and complex cardiac malformation.

Kant et al. (1998) described the Catel-Manzke syndrome in a female infant. The characteristic Pierre Robin sequence and deviation of the index finger, caused by an extra metacarpal, were described. This was said to have been the fifth female case; a total of about 25 cases had been reported to that date. Single cases were reported by Klug et al. (1983) and Petit et al. (1994) and sisters by Dignan et al. (1986).

Puri and Phadke (2003) reported a 13-year-old boy with prominent eyes, retrognathia, and low-set ears, as well as pectus excavatum, bilateral brachydactyly, and ulnar deviation of both index fingers. Radiologic examination of the hands showed abnormal proximal phalanges of the second digits. This case differed from classic Catel-Manzke syndrome in having isolated hand malformations without any other malformations, such as cleft palate or cardiac abnormalities. These authors suggested the term 'mandible digital syndrome.'

Manzke et al. (2008) presented 2 additional patients with the syndrome. One had mandibular hypoplasia, posterior displacement of the tongue resulting in obstruction, cleft palate, and rhomboid-shaped accessory bones between the second metacarpal and proximal phalanx, causing radial deviation of the index finger. The second child had micrognathia, ankyloglossia, cleft palate, and an accessory bone at the second metacarpal bilaterally.

In a review of the literature, Manzke et al. (2008) noted that in affected infants, the supernumerary deltoid or trapezoid bone is located on the ulnar side between the slightly shortened second metacarpal and the significantly shortened corresponding proximal phalanx. On the ulnar side, the accessory bone has a pin-shaped bone, probably an epiphysis, causing a broadening of the index finger at the level of the metacarpophalangeal joint. Not all patients with Catel-Manzke syndrome show the full range of the Pierre Robin anomaly, and Manzke et al. (2008) suggested that the term 'micrognathia-digital syndrome' is more accurate. Other features may include postnatal failure to thrive and growth delay due to airway obstruction. About 70% of children have additional severe congenital abnormalities, such as cardiac defects, and other skeletal features can include talipes, knee dislocation, and joint laxity. The origin of the extra bone between the second metacarpal and the corresponding proximal phalanx was unclear and remained a matter of debate.

Kapoor et al. (2011) reported a 2.5-year-old girl who presented with a large cystic hygroma. Physical examination showed short stature and low weight, high-arched palate, proptosis, posteriorly rotated ears, short neck, and hypertrichosis on the back and trunk. Her hands showed radial deviation of the index fingers and clinodactyly of the little fingers, and her feet were inturned with short toes. Radiographs showed a small mandible, an extra radially angulated bone at the distal end of the second metacarpal. Cleft palate was not present.

Ehmke et al. (2014) reported 2 unrelated children with Catel-Manzke syndrome and mutations in the TGDS gene (see MOLECULAR GENETICS). One was a 3.5-year-old girl, born of nonconsanguineous British and South American parents, who had thin eyebrows, mild hypertelorism, upslanting palpebral fissures, cleft palate, micrognathia, and bilateral hand abnormalities. Echocardiogram revealed a ventricular septal defect, and hand radiographs showed a triangular-shaped bone inserted between the second metacarpal and its proximal phalanx bilaterally, causing radial deviation of the index fingers. On the left hand, an additional pin-shaped ossification center was visible. The other affected child was a male infant, born to unrelated Cameroonian parents, who underwent intubation and ventilation in the neonatal period due to a Pierre Robin sequence with severe retrognathia and cleft palate. He also had bilateral radial deviation and clinodactyly of the second digit and a mild ulnar deviation of the third and fourth fingers; radiographs showed the typical Manzke dysostosis. Other features included wide anterior fontanel, low-set ears with prominent antihelices, short neck, short humeri and femora, adducted thumbs, and short toes.

Inheritance

A familial basis was suggested by Gewitz et al. (1978) and Stevenson et al. (1980).

Brude (1984) suggested X-linked recessive inheritance for Catel-Manzke syndrome.

Molecular Genetics

By exome sequencing followed by filtering for de novo or recessive mutations in 7 patients with Catel-Manzke syndrome, including the original patient described by Catel (1961) and Manzke (1966) and 4 other previously reported patients (Kant et al., 1998; Manzke et al., 2008; Nizon et al., 2012), Ehmke et al. (2014) identified homozygosity or compound heterozygosity for mutations in the TGDS gene (616146.0001-616146.0006). Sanger sequencing validated the mutations, which were present in heterozygosity in all available parental DNA.

Exclusion Studies

Manzke et al. (2008) excluded mutations in the GDF5 gene (601146) as a cause of Catel-Manzke syndrome.