HAND SYNDROMES
Cornelia de Lange Syndrome
K. Cheung, MSc, MD,* J. Upton, MD*
C
ORNELIA DE LANGE SYNDROME (Online Mendelian
Inheritance in Man #122470) is characterized
by ulnar dysplasia, facial hirsuitism with syn-
ophrys, and diminutive stature.1 Diagnosis can be made
prenatally based on sonographic findings of growth
retardation, limb defects, hirsuitism, and diaphragmatic
hernia. Alternative terminology includes Brachmann-
de Lange syndrome, de Lange syndrome, Amsterdam
syndrome, Typus Degenerativus Amstelodamensis
(new type of degeneration), and CDLS1. The syn-
drome’s eponym is attributed to Cornelia de Lange, a
pediatrician from Amsterdam who, in 1933, described
2 children with the condition. However, in 1916,
Brachman first described a child at autopsy with similar
but more severe features to this syndrome.2,3
ETIOLOGY
Incidence of Cornelia de Lange syndrome has been
estimated to range from 1 in 10,000 to 1 in 30,000
newborns. Most cases are sporadic, although some
families demonstrate autosomal dominance. A het-
erozygous mutation in the NIPBL gene, which encodes
for a component of the cohesion complex, on chro-
mosome 5p13.1 is responsible in 50% to 60% of cases.
Other identified gene mutations responsible for X-
linked or milder variants of Cornelia de Lange syn-
drome include SMC1A, SMC3, RAD21, and HDAC8.1
CLINICAL PHENOTYPES
This is a multisystem malformation syndrome, which
has very broad phenotypic variation. The diagnosis of
most children is usually obvious at birth, but owing to
the wide clinical phenotypic variation, many milder
forms of the syndromes often go unrecognized. The
most characteristic features involve the hands and the
From the *Department of Plastic and Oral Surgery, Boston Children’s Hospital, Boston, MA.
Received for publication June 28, 2015; accepted in revised form July 23, 2015.
No benefits in any form have been received or will be received related directly or
indirectly to the subject of this article.
Corresponding author: J. Upton, MD, 830 Boylston St., Suite 212, Chestnut Hill,
MA 02467; e-mail: jupton3@gmail.com.
0363-5023/15/---0001$36.00/0
http://dx.doi.org/10.1016/j.jhsa.2015.07.023
curious face. Severely affected children fail to thrive
and demonstrate significant mental compromise.
Common early problems include feeding difficulty,
seizures, irritability, a deep hoarse cry, and obvious
limb abnormalities.
Upper extremity anomalies
Ulnar dysplasia is the most frequent upper extremity
finding in Cornelia de Lange syndrome. Phenotypes
vary from partial to complete absence of the ulna,
radial dysplasia, and humeroradial synostosis.
The most characteristic hand finding is hypoplasia
on both ulnar and radial sides. The hand may contain
as few as one digit or as many as five. Ectrodactyly is
common with ulnar digits more often absent than
radial digits. A biphalangeal thumb on the radial side
of the hand is the most persistent single digit in a
monodactylous hand. Many of the two-digit hands
are unstable at the carpometacarpal level with simi-
larities to a typical cleft hand with a very deep central
cleft (Fig. 1). Many hands with two or three digits,
referred to as oligodactyly in the pediatric and genetic
literature, have soft tissue webbing connecting these
digits. Many of the thumbs lack thenar musculature
and a normal web space and in the pediatric literature
are called “proximal implantation thumbs.” Kirner
deformity of the fifth digit and a palmar simian crease
may also be observed2,4,5 (Fig. 1) Clinodactyly of the
fifth digit, when present, is present in 88% of these
children. Skeletal maturation is delayed. Carpal coa-
lition may involve both distal and proximal rows.6,7
When a hand is present, there is a characteristic
metacarpal profile in which the first digit is shorter
than the others, and the second and fifth are shorter
than the third and fourth. The middle phalanx of the
index finger is always hypoplastic.8
Phocomelia and antecubital pterygium may be pre-
sent, a condition distastefully referred to as “chicken
wingelike appendices” (radial head dislocation with
secondary elbow contracture).6 In these children, upper
limb posture typically involves an elbow stiff in
extension and a wrist flexed with ulnar deviation. The
flexion contracture of the elbow is typically unyielding.
In addition, the glenohumeral joint motion is usually
limited. These contractures are present at birth and
Ó 2015 ASSH r Published by Elsevier, Inc. All rights reserved. r 1
2 CORNELIA DE LANGE SYNDROME

FIGURE 1: Cornelia de Lange syndrome. A Craniofacial features include brachycephaly, hirsuitism, long curly upper and lower
eyelashes, a depressed nasal dorsum, anteverted nostrils, ptosis of the upper eyelids, low-set ears, and prominent synosphros. Not shown
is a unilateral complete cleft of the palate with a very high arch. Bilateral, asymmetrical upper limb anomalies with a marked reduction in
digits are also present. B Right upper limb with ulnar absence and present radius. Elbow ankylosed in full flexion. C Variable pre-
sentation of the forearm: complete ulnar absence (left), with radial bowing (center), and present ulna with radial head dislocation (right).
D Two-fingered hand consists of a thumb, first web space, triphalangeal index ray, and hypoplastic thenar intrinsic muscles (left). Kirner
deformity of the fifth digit (center). Two-fingered flail hand with no carpometacarpal support in a typical cleft hand appearance (right).

persist without surgery (Fig. 1). The contralateral limb and metatarsus adductus; talipes equinovarus, Legg-
may be normal but is usually affected. Perthes disease, and scoliosis have also been reported.4

Musculoskeletal anomalies Craniofacial

Additional musculoskeletal anomalies in Cornelia de Facial features in Cornelia de Lange syndrome are
Lange syndrome include toe syndactyly of the second web distinct and diagnosis is usually made easily. Bra-
space, toe hypoplasia, absence of the tibia, micromelia, chycephaly and synophrys are characteristics present

J Hand Surg Am. r Vol. -, - 2015

 CORNELIA DE LANGE SYNDROME
in all of these children. Common features also include
excess facial hair and generalized hirsutism, unusually
long curly eyelashes of the upper and lower eyelids,
and low anterior and posterior hairlines. Microcephaly,
small widely spaced teeth with delayed eruption, thin
upper lip, depressed corners of the mouth, and occa-
sional high-arched palate or cleft palate may also be
present. Patients have an upturned nose, depressed
nasal bridge, long philtrum, low-set ears, and short
neck (Fig. 1).
Ophthalmological findings include ptosis, nystagmus,
and myopia. Hearing loss is usually secondary to otitis
media.
Visceral
Patients frequently have gastroesophageal reflux dis-
ease and pyloric stenosis. Congenital heart disease,
including valvular pulmonary stenosis or left-to-right
shunt, may be present. Urogenital anomalies include
structural anomalies of the kidney and urinary tract, and
hypoplasia of male genitalia with undescended testicles
J Hand Surg Am.
3
and hypospadias. Common neurological manifestations
include mental retardation, language delay, and hyper-
tonicity. Endocrinopathies related to dysfunction of
gonadotropin and prolactin secretion may be observed.
REFERENCES
1. Kniffin C. Cornelia de Lange syndrome 1; CDLS1. OMIM. 2013. Avail-
able at: http://www.omim.org/entry/122470. Accessed May 11, 2015.
2. Rayan GM, Upton J III. Congenital Hand Anomalies and Associated
Syndromes. Berlin: Springer; 2014:155e158.
3. Kline AD, Krantz ID, Sommer A, et al. Cornelia de Lange syndrome:
Clinical review, diagnostic and scoring systems, and anticipatory
guidance. Am J Med Genet A. 2007;143A(12):1287e1296.
4. Roposch A, Bhaskar AR, Lee F, Adedapo S, Mousny M, Alman BA.
Orthopaedic manifestations of Brachmann-de Lange syndrome: a
report of 34 patients. J Pediatr Orthop B. 2004;13(2):118e122.
5. Jones K. Smith’s Recognizable Patterns of Human Malformation. 6th
ed. Philadelphia: Elsevier Saunders; 2006:82e87.
6. Temtamy SA, McKusick VA. The Genetics of Hand Malformations.
New York: Alan R Liss Inc.; 1978:149e154.
7. Poznanski AK, Pratt GB, Manson G, Weiss L. Clinodactyly, camp-
todactyly, Kirner’s deformity and other crooked fingers. Radiology.
1969;93(3):573e582.
8. Halal F, Preus M. The hand profile on de Lange syndrome: diagnostic
criteria. Am J Med Genet. 1979;3(4):317e323.
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