Agenesis of the corpus callosum and congenital lymphedema: A novel recognizable syndrome?
ABSTRACT We present double first cousins, a girl and a boy, with the uncommon association of agenesis of the corpus callosum and congenital lymphedema. Other features shared by both include oligohydramnios, similar facial dysmorphism, sacral dimple, developmental delay, and sociable personality. While some of these findings overlap with FG syndrome and Hennekam syndrome, the findings in our patients are sufficiently different to exclude these diagnoses. We propose that this is a new syndrome with presumed autosomal recessive inheritance.
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ABSTRACT: We have previously described an autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia (MED), and distinctive facies in a large, extended Omani family. The MED observed seems to be part of a larger malformation syndrome, since both craniofacial and central nervous system changes were present in the family. We performed a whole genome scan in this family in order to identify the gene locus for this malformation syndrome. Using homozygosity mapping, we show linkage to the telomeric region of the long arm of chromosome 15. The position of both the disease gene and the principal glycoprotein, chondroitin sulphate proteoglycan (aggrecan, AGC1) on chromosome 15q26, suggested that the aggrecan gene is a candidate for the disease in this family. However, three of the four affected children were heterozygous for a polymorphism at position 831 of the coding sequence of AGC1, providing strong evidence against its involvement. We have identified a gene locus for a recessive syndrome of macrocephaly, MED, and distinctive facies in a large Omani family. Aggrecan located on chromosome 15q26, within the critical region determined for this syndrome in this family, was excluded as a candidate gene.Journal of Medical Genetics 07/2001; 38(6):369-73. · 5.64 Impact Factor
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ABSTRACT: Microcephaly-lymphoedema-chorioretinal dysplasia (MIM 152950) has been described as a distinct clinical entity. The mode of inheritance is uncertain, but male to male transmission has been observed supporting autosomal dominant inheritance. A characteristic facial phenotype has recently been suggested. We report three isolated male patients with this condition who have all of the major features and share a distinct facial appearance with upslanting palpebral fissures, a broad nose with rounded tip, anteverted nares, long philtrum with thin upper lip, pointed chin and prominent ears. The clinical features in our patients support the hypothesis of a characteristic facial phenotype in this syndrome.Clinical Dysmorphology 08/2005; 14(3):109-16. · 0.42 Impact Factor
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ABSTRACT: Agenesis of the corpus callosum (AgCC), a failure to develop the large bundle of fibres that connect the cerebral hemispheres, occurs in 1:4000 individuals. Genetics, animal models and detailed structural neuroimaging are now providing insights into the developmental and molecular bases of AgCC. Studies using neuropsychological, electroencephalogram and functional MRI approaches are examining the resulting impairments in emotional and social functioning, and have begun to explore the functional neuroanatomy underlying impaired higher-order cognition. The study of AgCC could provide insight into the integrated cerebral functioning of healthy brains, and may offer a model for understanding certain psychiatric illnesses, such as schizophrenia and autism.Nature reviews. Neuroscience 05/2007; 8(4):287-99. · 31.38 Impact Factor
Agenesis of the Corpus Callosum and Congenital
Lymphedema: A Novel Recognizable Syndrome?
Mary C. O’Driscoll,1* Kim Jenny,2Sulagna Saitta,3William B. Dobyns,4and Karen W. Gripp2
1Medical Genetics Research Group and Regional Genetics Service, St Mary’s Hospital, Manchester, UK
2Division of Medical Genetics, Alfred I. DuPont Hospital for Children, Wilmington, Delaware
3Clinical Genetics Center, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
4Departments of Human Genetics, Neurology and Pediatrics, The University of Chicago, Chicago, Illinois
Received 19 March 2009; Accepted 25 October 2009
We present double first cousins, a girl and a boy, with the
uncommon association of agenesis of the corpus callosum and
congenital lymphedema. Other features shared by both include
oligohydramnios, similar facial dysmorphism, sacral dimple,
developmental delay, and sociable personality. While some of
these findings overlap with FG syndrome and Hennekam syn-
drome, the findings in our patients are sufficiently different to
with presumed autosomal recessive inheritance.
? 2010 Wiley-Liss, Inc.
Key words: congenital lymphedema; agenesis of the corpus
callosum; hypotonia; developmental delay; sacral dimple
We report on double first cousins, a girl and a boy, with the
uncommon association of agenesis of the corpus callosum and
congenital lymphedema along with developmental delay. We
propose that this condition represents a novel syndrome with
presumed autosomal recessive inheritance (Fig. 1).
Patient 1 (LR07-200a2) is the older of the cousins and her parents’
chromosome 22q11.2. Fetal echocardiogram was reported as
(C/S) due to pre-eclampsia and suspected placental insufficiency.
Severe intrauterine growth retardation (IUGR) was evident with a
birth weight of 962g (?4 SD) and occipito-frontal circumference
8 at 5min. She required oscillation ventilation due to pulmonary
hypertension and subsequently developed hyperglycemia and
thrombocytopenia. A persistent ductus arteriosus (PDA) closed
found on echocardiography. Renal ultrasonography showed a cyst
on the upper pole of the right kidney, but subsequent scans
including a micturating cystourethrogram were normal. Magnetic
resonance imaging (MRI) of her lumbar spine was normal at age
6 months with no evidence of a tethered cord or abnormal tract
from her sacral dimple. Ophthalmology assessment was normal.
Lymphedema of the lower limbs, especially her feet and external
genitalia, was noted at birth and had resolved by her most recent
(Figs. 2, 3, and 5) including dolichocephaly, wide anterior fonta-
nelle, short palpebral fissures, low-set and posteriorly rotated ears,
very friendly and sociable. Significant developmental delay includ-
at age 40 months. She required medical treatment for gastro-
4 months were: height 88.6cm (?2 SD), weight 12kg (?1.5 SD),
and OFC 46.6cm (?1 SD). Brain MRI at 6 months showed partial
agenesis of the corpus callosum (ACC) consisting of a small, short,
and very thin corpus callosum (Fig. 6).
Patient 2 (LR07-200a1) is the younger of two children whose
parents also had two miscarriages. Routine ultrasound at 16 weeks
Mary C. O’Driscoll, Genetic Medicine, Manchester Academic Health
University Hospitals, NHS Foundation Trust, St Mary’s Hospital,
Oxford Road, Manchester M13 9002, United Kingdom.
Published online 23 June 2010 in Wiley InterScience
How to Cite this Article:
Gripp KW. 2010. Agenesis of the corpus
callosum and congenital lymphedema: A
novel recognizable syndrome?
Am J Med Genet Part A 152A:1621–1626.
? 2010 Wiley-Liss, Inc.
genic bowel. A fetal echocardiogram showed a structurally normal
heart with a moderate right-sided pericardial effusion. This per-
sisted throughout pregnancy without evidence of hemodynamic
compromise. Increased nuchal thickening was seen which, like the
echogenic bowel, resolved on follow-up studies. Amniocentesis
showed a normal 46,XY karyotype. He was born by emergency
caesarean at 35 weeks gestation for severe oligohydramnios and
reduced fetal movements. Apgar scores were 8 at 1min and 8 at
9min. His birth weight was 2,195g (?2 SD), length 45.72cm
(?1.25 SD), and OFC 33.5cm (?1 SD). He required ventilation
for respiratory distress at less than 12hr of age, and pulmonary
birth showed right ventricular dilatation and hypertrophy with
tricuspid regurgitation, and resolution of the pericardial effusion.
His most recent echo at age 3 months showed normal results. No
jaundice, hyperglycemia, or seizures were evident in the neonatal
period. Spinal ultrasound was performed due to a sacral dimple.
Minimal pyelectasis was noted on ultrasound, and has since re-
global developmental delay and walked independently at age
27 months. At age 32 months he spoke about 20 single words, and
13kg (?0.5 SD), and OFC 50.4cm (þ0.5 SD) He has very similar
personality. Mild hypotonia has been present since birth. Exami-
nation revealed 5th finger clinodactyly and hypoplastic nails in
FIG. 1. Family tree, affected individuals are shaded in black. The probands’ grandparents are unrelated.
FIG. 2. FrontviewsofPatient1atage20months(left)andPatient2
atage12 months(right), noteepicanthalfolds,upturnedslightly
wide nasal tip and long philtrum with thin upper lip in both. [Color
figure can be viewed in the online issue, which is available at
FIG. 3. Facial profiles of Patient 1 at age 20 months (left) and
Patient2atage 12months (right), note normallyformedhelices.
FIG. 4. Left foot of Patient 2 as a neonate, showing severe edema.
1622AMERICAN JOURNAL OF MEDICAL GENETICS PART A
seen on cranial computed tomography (CT) scan. Electroenceph-
alogram and ophthalmology review were normal. He has experi-
enced difficulties with feeding since birth with episodes of
irritability and blood in the stool. GERD was diagnosed and has
responded to medical treatment.
Patient 2’s mother, was admitted 1 week after his delivery with
congestive heart failure attributed to pregnancy-related, dilated
discharged after 3 days. There was no evidence of liver disease or
platelet abnormalities in the peri-partum period and an echocar-
diogram 5 months post-delivery was normal.
anterior falx, mild hippocampal dysplasia with globular shape and
thick leaves, prominent cysts in the basal ganglia and mildly
enlarged and laterally displacedlateral ventricles.The gyral pattern
and cortex, and the brainstem and cerebellum appeared normal in
All investigations including newborn metabolic screening by tan-
dem mass spectrometry and genetic studies had normal results.
FIG. 5. Facial features of Patient 1 (left) age 3 years 4 months and
Patient 2 (right) age 2 years 8 months showing persistence of
facial features. [Color figure can be viewed in the online issue,
which is available at www.interscience.wiley.com.]
FIG. 6. Brain MRI in Patients 1 (A–D) and 2 (E–H). Midline sagittal images show partial agenesis consisting of a short, thin, and deformed corpus
callosum in Patient 1 (arrowheads in A) and complete agenesis in Patient 2 (arrowhead in E). The white asterisk in E is placed over a medially
levelofthelateralventriclesdemonstratedeficiencyofthefalxcerebriin both(blackasterisksinCandG) thatallowsinterdigitationofgyrifromthe
O’DRISCOLL ET AL.
22q11 and subtelomeres, PTPN11 and KRAS mutation analysis,
lysosomal enzymes, very long chain fatty acids and 7-dehydrocho-
No abnormality was noted on a 500,000 SNP comparative
genomic hybridization array and high resolution SNP microarray
analysis using the Affymetric 5.0 microarray on Patient 2.
Both patients were enrolled in an IRB approved research study
(University of Chicago #09202).
The patients reported here share numerous findings, including a
pregnancy history of oligohydramnios; resolving congenital
lymphedema and pulmonary hypertension, ACC, sacral dimple,
global developmental delay, facial dysmorphology, and cheerful
personality. After excluding an identifiable cytogenetic abnormali-
ty,wereviewed syndromespresentingwith thekey findingsseen in
our patients. The patients are double first cousins of opposite sex,
suggesting an autosomal recessive inheritance pattern for this
constellation of findings.
Primary lymphedema results fromfluid accumulationintissues
more common in males [Rockson, 2001] and can be a diagnostic
ly 20% of individuals with Noonan syndrome have evidence of
lymphatic dysplasia, commonly affecting the hands and feet and
features of Noonan syndrome, including ptosis and downslanting
palpebral fissures, cardiac malformations or increased skin pig-
mentation were lacking in our patients. Affected pregnancies are
often complicated by polyhydramnios, rather than oligohydram-
isnormal ormildly delayed.Noassociationbetweenoligohydram-
nios and lymphedema could be found in the current literature or
associated features, and inheritance pattern [Northup et al., 2003].
Karpanen and Alitalo  comprehensively reviewed its patho-
genesis and mouse models for lymphatic development but associ-
ateddevelopmental malformations were notmentioned.There are
major diagnostic component [Northup et al., 2003; Malik and
Grzeschik, 2008]. Lymphedema type I (Nonne–Milroy type) is
caused by mutations in the FLT4 gene (MIM153100) and charac-
terized by prenatal or childhood onset lymphedema without asso-
ciated malformations or facial anomalies [Milroy, 1892; Ferrell
distichiasis, and ptosis [Meige, 1898; Finegold et al., 2001] results
from heterozygous FOXC2 mutations (OMIM 153000/153200/
153300/153400; OMIM, 2009). In these patients lymphedema
develops around the onset of puberty, and involves the upper
limbs, face, and chest. Our patients do not have abnormal nails,
dominant resolving lymphedema and papillomatosis was mapped
to 6q16.2-q22.1 [Malik and Grzeschik, 2008]; however, no associ-
ated features consistent with our patients’ presentation were seen.
Although the latter report describes an unusual face there were no
malformations in other organ systems.
Vasudevan et al.  presented three cases of microcephaly–
condition, as in our patients, the lymphedema improves with age.
However, no structural brain abnormalities were seen in the four
[Abdel-Salam et al., 2000; Vasudevan et al., 2005]. The patients
described here do not have significant microcephaly, eye abnor-
malities, or similar facial features to MLCRD. Van Steensel et al.
 ascribed the name Irons–Bianchi syndrome to the combi-
nation of lymphedema, congenital heart defects, and characteristic
facies [Irons etal., 1996](OMIM601927). There aresome similar-
ities to our patients, namely prematurity, hydrops, and epicanthal
the patients in the original report, was described as progressive,
there were no developmental concerns and brain imaging was not
Hennekam lymphangiectasia–lymphedema syndrome (OMIM
235510) was first described as intestinal lymphangiectasia with
severe peripheral genital and facial lymphedema, facial dysmor-
and literature review by Van Balkom et al. , only one had a
callosal abnormality. This patient also had mildly enlarged lateral
of the lower limbs and eyelids present from birth. Repeated MRI
showed progressive brain atrophy and she developed a spastic
diplegia, tremor, and seizures. Van Balkom et al.  reported
the developmental level in Hennekam syndrome ranging from
normal to severely delayed, though in the majority the delay is
mild. The lymphedema is usually congenital and progressive with
frequent complications. The family described here shares some of
lymphangiectasia and characteristic facies.
Agenesis of the corpus callosum has been described as a finding
in patients with a wide spectrum of associated malformations,
syndromes and chromosomal abnormalities [Dobyns, 1996; Paul
et al., 2007], FG syndrome encompasses ACC and maps to at least
five regions on the X chromosome (OMIM 305450) and clinically
affected females and males have been seen [Battaglia et al., 2006].
clinical diagnosis of FG syndrome [Risheg et al., 2007; Schwartz et
al., 2007]. No carrier females with clinical manifestations were
reported. All six males with brain imaging studies showed
complete or partial absence of the corpus callosum. No mention
a number of other features not seen in FG syndrome, including
IUGR and oligohydramnios (Table I).
The Winter–Baraitser Dysmorphology Database lists a small
number of case reports where ACC and edema occurred together
[Ainsworth et al., 1997; Mortier et al., 1998; Bayoumi et al.,
2001]. None of these resemble the current family either facially or
in the spectrum of associated malformations. Case reports of
1624AMERICAN JOURNAL OF MEDICAL GENETICS PART A
ities can be found in the published literature [Avasthey and Roy,
1968; Dahlberg et al., 1983; Doffinger et al., 2001]. To our knowl-
seen in our patients.
databases looking for lymphedema and ACC resulted in three
case reports with chromosomal abnormalities. Genuardi et al.
 (ECARUCA #2385) reported a boy with ACC, peripheral
lymphedema, hypotonia, contractures and hypertelorism in asso-
ciation with an interstitial deletion of chromosome 3q13-q21.1 as
well as a further case with an overlapping deletion and ACC.
ECARUCA #4151 involves a female patient with developmental
hands and feet. Brain imaging (MRI) reportedly showed ACC and
delayed myelination. There are no published photographs but the
deletion of chromosome 9q34.3. The third published patient
[Wegner et al., 1996] (ECARUCA #3514) was also female. She had
facial dysmorphism, PDA, VSD and pulmonary stenosis, talipes,
polyhydramnios, intrauterine growth restriction (IUGR), digital
abnormalities, postnatalmicrocephaly,andtransient lymphedema
of the feet. A brain MRI showed ACC, cerebellar hypoplasia, and
ventriculomegaly. Her karyotype was 46,XX,der(11)t(6;11)-
(p21.3;q25)mat. None of the regions listed above overlap with
those of identifiable lymphedema syndromes in which causative
al., 2000; Karkkainen et al., 2000; Brice et al., 2005].
In conclusion, we present two related children with a novel
combination of developmental problems including oligohydram-
nios, lymphedema, and ACC, not matching any known syndrome.
genes for lymphedema and/or ACC, routine karyotyping and both
diagnostic BAC microarray and high resolution SNP analysis did
not show an abnormality. We are unable to discount imprinting
and an abnormality of the mitochondrial genome as possible
mechanisms of inheritance. The presence of an almost identical
combination of problems in first cousins of opposite sex with
normal parents suggests a single gene disorder with autosomal
recessive (AR) inheritance.
We are grateful to the family for allowing us to share their
information and to Dr. Tamim Shaikh for performing the CGH
array study on Patient 2.
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TABLE I. Comparison of Features in the Current Patients Compared to Patients Reported in the Medical Literature
Other lymphatic dysplasia
Posterior fossa abnormalities
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þ, Feature present; ?, feature absent; MLCRD, microcephaly–lymphedema–chorioretinal dysplasia; AR, autosomal recessive; AD, autosomal dominant; IUGR, intrauterine growth retardation.
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