CLINICAL REPORT

Catel–Manzke Syndrome: A Clinical ReportSuggesting Autosomal Recessive InheritancePelin Ozlem Simsek Kiper,* G€ulen Eda Utine, Koray Boduro�glu, and Yasemin AlanayPediatric Genetics Unit, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

Received 22 March 2011; Accepted 1 June 2011

We describe a 3-month-old male infant with cleft palate, glos-

soptosis,micrognathia, andbilateral clinodactyly, an association

which is characteristic of Catel–Manzke syndrome. In addition,

the patient had ligamentous laxity in the knee which is a rare

finding of this syndrome. The mode of inheritance of Catel–Manzke syndrome is unknown. Most cases are thought to be

sporadic but the present patient with consanguinity between

the parents and a possibly affected sib provide support for

autosomal recessive inheritance. � 2011 Wiley-Liss, Inc.

Key words: Catel–Manzke syndrome; cleft palate; autosomal

recessive inheritance; Pierre Robin sequence

INTRODUCTION

Catel–Manzke syndrome is a rare genetic disorder characterized by

the association of Pierre Robin sequencewith digital abnormalities.

It was first described in 1961 byCatel who reported on a 6-week-old

male infant with cleft palate, glossoptosis, micrognathia, and an

accessory ossification center at the base of the proximal phalanx of

the index finger leading to bilateral clinodactyly. In 1966, Manzke

reported additional details on the same patient, noting that the

supernumerary ossification center was a distinct form of hyper-

phalangism. Further descriptions of cases involving finger anoma-

lies in associationwithPierreRobin sequence led to thedefinitionof

this condition,whichwas given thenameCatel–Manzke syndrome.

The mode of inheritance of this rare syndrome is still unknown.

Themajority of reported patients have beenmale but an increasing

number of female patients are being reported, making an X-linked

inheritance unlikely. The present patient has classical features of the

Catel–Manzke syndrome. In addition, he has ligamentous laxity in

the knee. The consanguinity between the parents and the presence

of another affected sib in the family suggest autosomal recessive

inheritance.

CLINICAL REPORT

A 3-month-old male infant was referred to the clinic with atypical

facial features and cleft palate. The patient was born to healthy

consanguineous parents (Fig. 1). Themother was 23 and father was

28 years old. Mother’s height and body weight were 163 cm (75th

centile) and 60 kg (75th centile), respectively and her head circum-

ference was 55 cm (mean); father’s height and body weight were

170 cm (25th centile) and 80 kg (90–97th centile), respectively. His

head circumference was 56 cm (mean). Both the mother and the

father did not have any systemic diseases. Their clinical examina-

tions including cardiovascular, respiratory, genitourinary, gastro-

intestinal, and nervous systemswere normal. The first pregnancy of

this couple was a term female who died on the postnatal 13th day.

She had short extremities, cleft palate, and vertebral anomalies. The

second pregnancy was an intrauterine demise lost at term. This

female fetus also had short extremities and kyphoscoliosis. The

third pregnancywas a spontaneous abortion. The fourth pregnancy

was the present patient. Prenatally, nuchal edema and polyhy-

dramnios were noted in the second trimester of the present

patient. Detailed fetal ultrasonography showed bilateral clinodac-

tyly, shortness in the extremities, and scoliosis. Amniocentesis

revealed 46, XY. Medical termination was suggested but the family

declined.

The patient was born at term, via normal delivery, with a birth

weight of 3,000 g (25th centile). No resuscitation was required

initially but later on he had cyanosis and difficulty in breathing. He

was then noted to have a cleft palate. After the improvement of

respiratory distress and stabilization of the patient, he was referred

to our hospital for further evaluation. At admission, body weight

was 2,800 g (<3rd centile), length was 44.5 cm (<3rd centile), and

head circumference was 37 cm (25th centile). He had eye contact

but no head control yet. On physical examination broad base to

nose, cleft palate, glossoptosis, micro-retrognathia, narrow thorax,

*Correspondence to:

Pelin Ozlem Simsek Kiper, M.D., Pediatric Genetics Unit, Hacettepe

University, _Ihsan Do�gramacı Children’s Hospital, Sihhiye 06100,

Ankara, Turkey. E-mail: pelinozlem@hacettepe.edu.tr

Published online 10 August 2011 in Wiley Online Library

(wileyonlinelibrary.com).

DOI 10.1002/ajmg.a.34163

How to Cite this Article:Kiper POS, UtineGE, Boduro�gluK, Alanay Y.2011. Catel–Manzke syndrome: A clinical

report suggesting autosomal recessive

inheritance.

Am J Med Genet Part A 155:2288–2292.

� 2011 Wiley-Liss, Inc. 2288

pectus carinatum, bilateral clinodactyly, and ligamentous laxity in

the knee were noted (Fig. 2). He had a systolic cardiac murmur.

Cardiac examination by color Doppler echocardiography revealed

a secundum atrial septal defect and patent ductus arteriosus

requiring no medical intervention. Radiographs of both hands

and feet revealed metacarpophalangeal and metatarsaphalangeal

extra ossification centers (Figs. 3 and 4). Radiographs of the lower

extremities and spine were normal (Fig. 5A,B). The patient was

clinically and radiographically diagnosed as Catel–Manzke

syndrome.

DISCUSSION

Catel–Manzke syndrome is rare, and characteristic hallmarks

include Pierre Robin sequence, bilateral hyperphalangy, and

clinodactyly of the index finger. Typical hand abnormality is

bilateral shortening and radial deviation of the index finger due

to an accessory bone at the metacarpophalangeal joint. The

FIG. 1. The pedigree of the patient.

FIG. 2. Facial phenotype of the patient. Note micro-retrognathia, full

cheeks, low-set ears with helix malformation, narrow thorax,

abdominal distention, digital abnormalities of both hands and feet,

loose skin, and midline cleft of the soft palate. [Color figure can be

seen in the online version of this article, available at http://

onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

FIG. 3. Digital abnormalities of both hands. Note clinodactyly of

index, third and fourth fingers of right hand along with clinodactyly

of index and fourth fingers of left hand. Extrametacarpophalangeal

ossifications can be seen in the radiograph. [Color figure can be

seen in the online version of this article, available at http://

onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

KIPER ET AL. 2289

hyperphalangism in Catel–Manzke syndrome is a distinct form of

hyperphalangism as Manzke first discussed in 1966. The present

patient withmicrognathia, glossoptosis, cleft palate, and associated

upper respiratory obstruction, together with digital defect readily

fulfills the diagnostic criteria for Catel–Manzke syndrome.

There are over 30 reported cases of Catel–Manzke syndrome,

some of which do not fulfill the criteria of this specific syndrome

[Manzke et al., 2008]. Pierre Robin sequence, which is an associated

finding in about 80% of cases, is normally a combination of

micrognathia and glossoptosis, with or without cleft palate

[Sheffield et al., 1987]. Not all patients affected with Catel–Manzke

Manzke syndrome show the full range of this sequence [Thompson

and Winter, 1986; Puri and Phadke, 2003; Clarkson et al., 2004;

Manzke et al., 2008]. Therefore, we agree withManzke et al. [2008]

that the term ‘‘palato-digital syndrome’’ is incorrect and should

be replaced by the term ‘‘micrognathia-digital syndrome’’ if an

alternative to Catel–Manzke is to be preferred. The present patient

had cleft palate, micrognathia, and glossoptosis typically showing

the full range of Pierre Robin sequence.

About 70% of the patients with Catel–Manzke syndrome are

known to have additional congenital abnormalities [Manzke et al.,

2008]. Congenital heart defects are reported in 40% of cases [Puri

and Phadke, 2003]. Our patient had secundum atrial septal defect

and patent ductus arteriosus requiring no medical intervention.

He also had pectus carinatum. Thoracic deformities, such as pectus

carinatum and pectus excavatum, have been reported along with

congenital heart defects in Catel–Manzke syndrome [Stevenson

et al., 1980].Kneedislocationand talipes equinovarus in association

with Pierre Robin sequence were described before [Thompson and

Winter, 1986].Thepresent patient alsohadprominent ligamentous

laxity specifically in the knee.

Skeletal abnormalities such as index delta phalanx, clinodactyly

of the fifth finger, and an extra delta phalanx at the base of the

third phalanx are very common and among the hallmarks of this

syndrome. Metatarsal and toe abnormalities, bifurcation of first

metatarsal, hypoplastic proximal phalanx hallus, or short toes can

also be seen. There is resemblance between the hyperphalangy

phenotype in Catel–Manzke syndrome and isolated brachydactyly

type C which is caused by GDF5 mutations in the majority

of patients. However sequencing of three genes involved in

brachydactyly including GDF5, BMPR1B, NOG revealed no caus-

ative mutations in three Catel–Manzke patients [Manzke et al.,

2008].

Desbuquois dysplasia (DBQD), which is characterized by severe

prenatal andpostnatal growth retardation (<�5 SD), short stature,

joint laxity, progressive scoliosis, and advanced carpal ossification

with a delta phalanx should be kept in mind in the differential

diagnosis. DBQD shares some of the clinical features, such as hand

and foot changes and cleft palate, with Catel–Manzke syndrome.

The main radiological features in DBQD are short long bones with

metaphyseal splay, a ‘‘swedish key’’ appearance of the proximal

femur (exaggerated trochanter), and advanced carpal and tarsal

bone age with a delta phalanx [Desbuquois et al., 1966; Faivre et al.,

2004] which were not present in this patient. Figure 5A,B demon-

strate normal proximal femora and absence of platyspondyly.

Several distinct mutations in the Calcium-Activated Nucleotidase

1 gene (CANT1) have been identified in individuals with DBQD

[Huber et al., 2009; Faden et al., 2010]. However,CANT1mutation

analysis was negative in a patient with Catel–Manzke syndrome

[Cormier-Daire, personal communication].

TThe occurrence of several affected individuals within families

suggests an underlying genetic cause but the mode of inheritance is

still unclear. The rarity of female patients initially reported

suggested an X-linked pattern of inheritance. However, an increase

in the number of reported female patients makes this unlikely.

Although most cases are sporadic, five familial cases with various

relationships have been reported so far [Manzke et al., 2008]. No

chromosomal abnormalities were described in the reported cases.

The present patient and his family also represent one of the familial

cases. The first-born baby of this couple had short extremities, cleft

palate, and vertebral anomaly. It is not known whether the first-

born had the typical finger anomalies but it is likely that she had the

Catel–Manzke syndrome, which would suggest an autosomal

recessive inheritance.

The second pregnancy of this couple, which resulted in utero

exitus at term, also had short extremities andkyphoscoliosis, butwe

have no information onwhether cleft palate or finger anomaly were

observed. In the earlier literature an infant with Catel–Manzke

syndrome was reported whose stillborn brother had Pierre Robin

sequence and atrial septal defect, but it was not known whether he

had the typical finger abnormality or not [Gewitz et al., 1978]. The

authors suggested that the latter sib also had the Catel–Manzke

FIG. 4. Digital abnormalities of both feet. Note deviation and

clinodactyly of the fifth toes of both feet. There is a wide gap

between the fourth and the fifth toes. Extrametatarsal

ossifications can be seen in the radiograph. [Color figure can be

seen in the online version of this article, available at http://

onlinelibrary.wiley.com/journal/10.1002/(ISSN)1552-4833]

2290 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

syndrome, which would suggest autosomal or X-linked recessive

inheritance [Gewitz et al., 1978].

The family andpatientwe report onherewith consanguinity and

affected siblings of both genders support previous suggestions of

autosomal recessive mode of inheritance. Until the underlying

molecular mechanism is clear, we suggest caution when counseling

families with a single affected child.

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FadenM, Al-Zahrani F, Arafah D, Alkuraya FS. 2010. Mutation of CANT1causes desbuquois dysplasia. Am J Med Genet Part A 152A:1157–1160.

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Gewitz M, Dinwiddie R, Yuille T, Hill E, Carter CO. 1978. Cleft palate andaccessory metacarpal of index finger syndrome: Possible familial occur-rence. J Med Genet 15:162–163.

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FIG. 5. A: Radiograph of frontal view of the lower extremities and spine. B: Radiograph of lateral view of the lower extremities and spine.

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