RESEARCH ARTICLE

Adams–Oliver Syndrome: Additions to the ClinicalFeatures and Possible Role of BMP PathwayShankar Baskar,1 Muralidhar Laxmanrao Kulkarni,1* Akhil Muralidhar Kulkarni,2

Suhasini Vittalrao,1 and Preethi Muralidhar Kulkarni1

1Department of Pediatrics, JJMMC, Davangere, Karnataka, India2Department of Radiology, JJMMC, Davangere, Karnataka, India

Received 28 January 2009; Accepted 22 April 2009

We report on a patient with Adams–Oliver syndrome, a condi-

tion characterized by scalp and limb defects. In addition we

noted in our patient a significant delay in the bone age and an

abnormal distal phalanx in one of her fingers manifesting

clinically as a broad finger tip. Both these features hitherto

unreported add to the phenotypic spectrum of the condition.

The underlying etiopathogenesis of this condition has remained

in the domain of hypothesis, with none being conclusive. Based

on the characteristic features of AOS and our report of delayed

bone age, we postulate a role played by the bone morphogenetic

protein pathway in the causation of this enigmatic condition. In

the background of this postulation and the report of an unusual

hand anomaly, a literature review on the various pathogenetic

mechanisms and anomalies of the hand reported in AOS is

presented. � 2009 Wiley-Liss, Inc.

Key words: Adams–Oliver syndrome; limb reduction defect;

cutis aplasia; finger phalanges; bone age measurements; bone

morphogenetic proteins; metacarpophalangeal pattern profile

INTRODUCTION

Adams–Oliver syndrome (AOS) (OMIM 100300) is a rare but

frequently reported condition characterized by congenital absence

of skin, known as ‘‘aplasia cutis congenita’’ usually limited to the

scalp vertex and terminal transverse limb defects [Adams and

Oliver, 1945]. Although first described by Forrest Adams and Peter

Oliver in 1945, similar conditions have been observed much earlier,

dating back to 1910 [Whitley and Gorlin, 1991]. The condition has

variable expression, with scalp lesions varying in size and depth

often associated with skull defects, while the limb defects range

from distal tapering to hemimelia [Farrell et al., 1993]. While the

predominant inheritance pattern seems to be autosomal dominant

with several instances of non penetrance; autosomal recessive and

sporadic cases have been reported [Mempel et al., 1999]. Although

several hypotheses have been made, the precise pathogenetic

mechanism of AOS remains uncertain [Papadopoulou et al., 2008].

We report on a patient with characteristic features of AOS, who

was noted to have a broad fingertip in her right middle finger and a

significantly delayed bone age. To the best of our knowledge, both of

these features have not been reported or sought for previously and

hence adds to the phenotypic spectrum of this condition. The

presence of these unique findings in addition to the other reported

features of AOS, made us speculate on the possibility of a role played

by the bone morphogenetic proteins (BMP) in the etiopathogenesis

of this enigmatic condition. In the background of our report of

these new features and hypothesis of the BMP pathway in AOS;

we have reviewed the literature on the suggested pathogenetic

mechanisms and reported anomalies of the hand.

CLINICAL REPORT

Our patient, a 4-year-old girl is the second child of a consangui-

neous (uncle-niece marriage) 28-year-old father and 26-year-old

mother, from southern India. She was brought to our hospital

outpatient department incidentally along with her brother, who

had come for regular immunization. She was born of a full

term, uncomplicated pregnancy in a primary health care center.

Information regarding her birth weight, head circumference and

APGAR scores were not available. At birth she was found to have a

large defect in the scalp which was found to be ulcerated with severe

bleeding; it was managed conservatively with regular dressing and

topical antibiotic creams. The defect had healed according to the

mother by 3 months of age, but had left a scarred patch with no

*Correspondence to:

Muralidhar Laxmanrao Kulkarni, Department of Pediatrics, JJMMC,

Davangere, Karnataka 577004, India. E-mail: kulakarniml@yahoo.com

Published online 15 July 2009 in Wiley InterScience

(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.32938

How to Cite this Article:Baskar S, Kulkarni ML, Kulkarni AM,

Vittalrao S, Kulkarni PM. 2009.

Adams–Oliver syndrome: Additions to the

clinical features and possible role of BMP

pathway.

Am J Med Genet Part A 149A:1678–1684.

� 2009 Wiley-Liss, Inc. 1678

growth of hair. There was no history of any surgery being done to

correct the defect. The mother also reported that even minor

trauma would lead to ulcerations in the scarred area and that the

child had one such ulcer at present. The child was noted from the

early neonatal period to have anomalies of the toes and inequality in

her right hand fingers. The right hand middle finger was also noted

to be larger in comparison with the rest, with no alterations in this

relation over the duration of the child’s lifetime. These anomalies

did not hinder in the normal functioning and development of the

child and hence no medical or surgical opinion had been sought.

There was no history of skin lesions similar to cutis marmorata

telangiectasia congenita (CMTC) (OMIM 219250), seizures or

cardiac complaints. All her developmental milestones were normal

for age and she scored 95 on the Binet-Kamat scale of intelligence

(Indian adaptation of the 1934 version of Stanford-Binet Scale of

intelligence) [Kamat, 1967]. She was currently attending primary

school.

On examination she was of normal stature, with a height of 98 cm

(estimated between the 15th and 50th centile, WHO standards) and

a weight of 18 kg (estimated at the 85th centile, WHO standards).

The upper to lower segment ratio was estimated to be 1.25. The scalp

showed a large 12 cm� 11 cm area of atrophic skin with patchy

areas of hair growth and an ulcer over the posterior part of the defect

(Fig. 1A). Palpation of the scalp revealed bilateral small underlying

skull defects over the parietal bone with an open anterior fontanel.

No prominent scalp veins or facial dysmorphism were noted. Oral

cavity was normal with appropriate dentition for age. Examination

of the upper limbs showed tapering of the fingers except in the right

middle finger which we observed to have a broad fingertip (Fig. 2A).

The term macrodactyly was not used in describing the anomalad

since the abnormality was restricted to the distal part of the finger

[Biesecker et al., 2009]. In the lower limbs varying degree of

short to partial absence of toes was noted with hypoplasia to

complete absence of toe nails (Fig. 3A). Other than these no other

abnormalities were noted and the systemic examination including

the genitalia was normal.

A Cranial CT with skull reconstruction revealed asymmetrical

defects in the parietal bones, which had ragged margins and an open

anterior and posterior fontanel (Fig. 1B). The brain parenchyma

showed normal attenuation. Radiography of the upper limbs

revealed shortening of the distal phalanges in all the fingers except

in the right middle finger which was broader compared to the other

phalanges and was noted to be ‘bifid’ (Fig. 2A). Since we noticed

that there was a discordance between the age of the patient and

the number of carpal bone, bone age estimation was performed

according to the Greulich and Pyle method, which was significantly

delayed (2 years 6 months compared to 4 years chronological age)

[Greulich and Pyle, 1959]. Due to the presence of the delay in bone

age, our patient underwent endocrinological assessment including,

thyroid function, growth hormone stimulation after clonidine

administration, leutinizing hormone and follicular stimulating

hormone levels estimation; all were within normal limits for age.

In view of the digital anomalies a metacarpophalangeal profile

pattern corrected for the closest bone age (3 years) was done for

both the hands (Fig. 4), which objectified the presence of shortening

of the distal phalanges with the exception of the right third distal

phalanx which was relatively longer compared to that of the other

fingers and also to that of the mean. The profile pattern was done

according to the guidelines set forth by Poznanski et al. [1972], and

using standards for metacarpal and phalangeal lengths set by Garn

et al. [1972]. The lower limb radiography revealed absence of all

distal phalanges (Fig. 3B).

Taking into consideration the characteristic combination of

findings, a diagnosis of AOS was made. Brain MRI, ultrasound of

the abdomen and echocardiography were done to rule out the

presence of known associations of AOS, which were all normal. In

view of the possible autosomal recessive inheritance pattern of the

condition [Tekin et al., 1999], and the presence of consanguinity in

the parents, a detailed examination of the patient’s mother, father

and of her two siblings, an elder sister and a younger brother was

done which revealed no abnormality suggestive of AOS. Radiogra-

phy revealed normal skull vaults and hand bones in the siblings and

FIG. 1. A: View of patient’s scalp lesion showing a 12 cm� 11 cm

atrophic skin area with an ulcer in the posterior aspect. B: CT

reconstruction of the cranial vault showing multiple bilateral

defects with ragged margin with patent anterior and posterior

fontanel.

BASKAR ET AL. 1679

parents. No delay in bone age was noted in the hand roentograms of

the siblings who were aged 7 and 2. A three generation family history

did not bring to light any other members of the family having

features of AOS or short stature. We consider that our patient is an

example of a sporadic occurrence of AOS, though an autosomal

recessive pattern of inheritance cannot be excluded.

DISCUSSION

The hallmark features of AOS are the limb and scalp defects. The full

spectrum of observed defects varies from hypoplastic nails to

transverse reduction defects that may present as hemimelia as

described by Adams and Oliver [1945] in their original report. In

addition to the transverse reduction limb defects, various other

anomalies involving the hand have also been reported (Table I). The

presence of a broad fingertip with an underlying bifid distal phalanx

in the present report, hitherto unreported in AOS adds to the

phenotypic spectrum of this condition.

The assessment of bone age has not been done in any of the

previous case reports to the best of our knowledge, although it

might not have been possible in patients with significant transverse

reduction defects. The presence of a delay in the bone development

in our patient cannot be attributed to the terminal transverse

reduction defects, since the abnormality was restricted to the distal

phalanges, whereas the other phalanges and the metacarpals were

normal in shape. Hence the noted aberration signifies the delay in

the skeletal development as a whole. Though our patient was of

normal stature for age, there was significant discordance between

her height and weight. Short stature has also been well documented

in previous case reports [Toriello et al., 1988], though the cause for

this was not elucidated. The bone age delay if confirmed in future

case reports or retrospectively in prior reports of AOS, could add to

the phenotypic spectrum of AOS.

AOS has been a ‘‘syndrome of hypotheses’’ with many postu-

lations for the underlying pathogenesis [Table II]. In their original

description of the syndrome, Adams and Oliver [1945] suggested

that the underlying pathology could be one of arrested development

or an agenesis of certain parts of the skeleton and soft tissue. Hoyme

FIG. 2. A: View of patient’s hands showing mild distal tapering in all of

the fingers except in the right middle finger which shows a broad

fingertip. B: Radiography of the hands showing shortening of the

distal phalanges in all the fingers except the right middle distal

phalanx which is relatively longer, broad and bifid. Note the delay

in bone age with decreased carpal bones.

FIG. 3. A: View of patient’s feet showing varying degrees

of shortening of the toes with nail hypoplasia. B:

Radiography of the feet demonstrating absent distal phalanx in all

the toes.

1680 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

et al. [1982] proposed that in utero vascular thrombotic accidents

causing interruption of blood supply to developing structures as

a pathogenesis. This was further supported by Der Kaloustian

et al. [1991] and Girard et al. [2005]. Vascular disruption as a

pathogenesis was put forward by Toriello et al. [1988] which was

strengthened by the association of dilated scalp veins [Whitley

and Gorlin, 1991], constriction rings [Keymolen et al., 1999],

pulmonary hypertension (PHT) [Swartz et al., 1999], periventri-

cular leukomalacia [Papadopoulou et al., 2008], and retinal folds

[Prothero et al., 2007].

Patel et al. [2004] suggested that abnormal pericyte recruitment

could be the unifying etiology for AOS. One of the evidence quoted

for this ‘‘pericyte hypothesis’’ was the model of ALK1-deficient

mice which shows poor migration, recruitment and proliferation of

pericytes. Mutations of the same gene in humans have been

implicated in hereditary hemorrhagic telangiectasia type 2 (HHT

2) (OMIM 600376) [Trembath et al., 2001], which is also associated

with PHT.

Seven candidate genes have been studied for disease causing

mutations by Verdyck et al. [2003, 2006]. These include MSX 2,

ALX4, MSX1, CART1, RUNX2, HOXD13, and P63. None of these

genes harbored any mutations and were effectively ruled out as the

putative cause for AOS.

The wide spectrum of anomalies in AOS, along with our report of

delayed bone age, points towards an underlying gene defect

that leads to ‘‘aberrant morphogenesis,’’ rather than resulting in

vascular disruption in isolation. A morphogen is defined as a

molecule distributed in a gradient that alters the developmental

fate of target cells in a concentration dependent manner [Hogan,

1996]. There is strong genetic and experimental evidence that the

group of BMPs regulate growth, differentiation, chemotaxis and

apoptosis, and play a pivotal role in the morphogenesis of a variety

of tissues and organs [Hogan, 1996]. BMPs are members of the

transforming growth factor-b (TGF-b) superfamily with more than

20 BMP-related proteins having been identified [Miyazono et al.,

2005]. In the following discussion we present evidence from the

literature linking the attributes of AOS with the BMP pathway,

including delayed bone age.

SCALP AND LIMB DEFECTS

Conditional knockout mouse of Transforming growth factor

receptor beta 2 (TGFBR2) show a strikingly similar phenotype to

that of ACC [Zehnaly et al., 2007]. The importance of BMP

signaling at multiple stages of dermal osteogenesis has also been

well documented, with homozygous mice mutants in BMP7 and

BMP4 having skull vault defects [Abzhanov et al., 2007]. The group

of brachydactylies, including brachydactyly type A2, type B and type

C/symphalangism-like phenotype have been associated with the

BMP pathway [Lehmann et al., 2003, 2006, 2007; Seemann et al.,

2005]. Similarities with digital anomalies of AOS, such as limb

reduction defects are evident in the mice and chicken embryo

models of these conditions.

CMTC and PHTCMTC occurs in about 25% of the patients with AOS [Borg and

Pfeifle, 1992]. As noted previously it shares pathological features

TABLE I. Anomalies of the Hand Other Than Transverse

Reduction Defects

Hemimelia Adams and Oliver [1945]Adactyly Adams and Oliver [1945]Syndactyly Whitley and Gorlin [1991]Zygodactyly Sybert [1985]Brachydactyly Sybert [1985]Ectrodactyly Bonafede and Beighton [1979],

Wilson and Harcus [1982]Polydactyly Fryns and Van den Berghe [1979]Broad fingertip Present report

FIG. 4. Metacarpophalangeal pattern profile of both the hands, corrected to the closest bone age (3 years). Note the shortening of the distal phalanges

except in the right 3rd distal phalanx which is relatively longer.

BASKAR ET AL. 1681

with HHT, which is caused by mutation in ALK1, a receptor for not

only TGF-Beta but also for BMP 9, 10 [David et al., 2008]. The BMP

receptor signaling has also been considered indispensable for the

establishment and maintenance of a mature, stable vasculature

[Liu et al., 2007] and hence its role in AOS, which has long been

considered to be secondary to a vascular disruption [Toriello et al.,

1988] seems putative, with CMTC adding evidence. PHT, an

association with AOS [Toriello et al., 1988; Swartz et al., 1999;

Patel et al., 2004; Piazza et al., 2004], has had strong implications in

the pathogenesis. Primary pulmonary hypertension (PPH1)

(OMIM 178600) has been found to be due to a mutation in BMPR2,

which causes abnormal pulmonary vascular smooth muscle cells,

which are resistant to growth inhibitory effects of BMP 2, 4, 7, and

TGF-Beta [Davies and Morrell, 2008]. Based on the similarities

between the pathological features noted by Patel et al. [2004] in

PHT associated with AOS and that of PPH1 and HHT2, a role of

BMP pathway in AOS seems extremely likely.

CARDIOVASCULAR MALFORMATIONS (CVM)

CVMs occur in approximately 20% of the patients with AOS, the

most common being obstructive lesions of the left heart, tetrology

of Fallot and ventricular septal defect [Lin et al., 1998]. It has been

suggested that genes known to be related to left sided obstructive

CVMs, such as the Notch signaling pathway, should be considered

for future molecular study in AOS [Digilio et al., 2008]. BMPs play a

critical role in cardiac development, and are crucial in the regula-

tion of septovalvular and cardiac outflow tract development

[Kaartinen et al., 2004; Van Wijk et al., 2007]. The Notch signaling

pathway implicated in CVMs associated with AOS, also acts

synergistically with TGFb/BMP to regulate their common target

genes [Guo and Wang, 2009].

DELAYED BONE AGE

The ossification centers of the skeleton appear and progress in a

predictable sequence in normal children, and skeletal maturation

can be compared with normal age-related standards. This forms the

basis of ‘‘bone age’’ or ‘‘skeletal age,’’ the only readily available

quantitative determination of net somatic maturation and, thus, a

mirror of the tempo of growth and maturation. It is not clear what

factors determine this normal maturational pattern, but it is certain

that genetic factors and multiple hormones, including thyroxine,

growth hormone, and gonadal steroids, are involved [Reiter and

Rosenfeld, 2008]. We attribute the delay in bone age in our patient

to be a manifestation of AOS, since other causes were ruled out by

biochemical tests. Of interest, Costa et al. [1998] reported a delay in

bone age in a 4-year-old boy; who was an obligate heterozygote of

Grebe chondrodysplasia (OMIM 200700). They considered the

delay in bone age to be a manifestation of the heterozygous

state. The gene defect in Grebe chondrodysplasia has been identified

to involve GDF5; which is closely related to the BMPs [Thomas

et al., 1997]. In addition heterozygous individuals of Grebe chon-

drodysplasia show similarities with AOS, such as polydactyly and

brachydactyly [Thomas et al., 1997]. Other possible evidence for the

role of BMPs in delayed bone age has been provided by Govoni

et al. [2006]. Their whole genome microarray analysis of growth

hormone-induced gene expression in bone, supported the possi-

bility of cross talking between major signaling pathways (i.e., Wnt,

BMP, and IGF) in mediating growth hormone effects in bone.

CONCLUSION

Verdyck et al. [2006] concluded that future candidate studies

should include genes with functions in limb and skull development

and in vasculogenesis/angiogenesis. We have stated evidence for the

BMPs to be involved in these functions. Given the pleiotropic

nature of the BMPs and the cross talking between the BMPs and

other members of TGF b superfamily including the intra and extra

cellular modulators [Reddi, 2001; Miyazono et al., 2005]; the key to

the underlying genetic basis of AOS, may lie in genes controlling

proteins in the common pathway, such as the SMADs and the BMP

receptors. These if targeted for future candidate gene studies, could

finally unravel the true etiology of this ‘‘syndrome of hypothesis.’’

ACKNOWLEDGMENTS

We sincerely thank the patient, her siblings, and parents for their

kind cooperation and enthusiasm during the course of the study.

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