Clin Genet 2010: 78: 227–235Printed in Singapore. All rights reserved

© 2010 John Wiley & Sons A/SCLINICAL GENETICS

doi: 10.1111/j.1399-0004.2010.01470.x

Original Article

Do children with Adams-Oliver syndromerequire endocrine follow-up? New informationon the phenotype and management

Kalina MA, Kalina-Faska B, Paprocka J, Jamroz E, Pyrkosz A, Marszał E,Małecka-Tendera E. Do children with Adams-Oliver syndrome requireendocrine follow-up? New information on the phenotype and management.Clin Genet 2010: 78: 227–235. © John Wiley & Sons A/S, 2010

Adams-Oliver syndrome (AOS) is a rare genetic condition in which themain diagnostic criteria are terminal transverse limb defects and aplasiacutis congenita. Within the spectra of the clinical phenotype of AOS,anthropometric abnormalities have also been reported. We present growthpattern along with hormonal assays in three patients with AOS, one beingtreated with growth hormone (GH). In Patient 1 (a boy, age 1.9 years),with delayed psychomotor development, epilepsy, deficits of body massand height, cryptorchidism, low insulin-like growth factor (IGF-1) levelswere found and magnetic resonance imaging (MRI) revealed hypoplasia ofmidline structures of the central nervous system (CNS). In Patient 2(a girl, age 3.6 years) no significant abnormalities in development, bodymass, height or neuroimaging were found. In Patient 3 (a girl, age8.2 years), with delayed psychomotor development and short stature, lowIGF-1 levels and partial GH deficiency were found; MRI revealed smallpituitary and polymicrogyria. The girl started GH treatment, improvingheight velocity and gross coordination. Based on these observations, itseems that intensity of auxologic and hormonal deficits in children withAOS is associated with CNS lesions. Hence, there are indications forneuroimaging and interdisciplinary follow-up of psychomotordevelopment, growth and puberty in this subset of patients with AOS.

MA Kalinaa, B Kalina-Faskaa,J Paprockab, E Jamrozb,A Pyrkoszc, E Marszałb andE Małecka-Tenderaa

aDepartment of Pediatrics, PediatricEndocrinology and Diabetes, MedicalUniversity of Silesia, Katowice, Poland,bDepartment of Pediatric Neurology,Medical University of Silesia, Katowice,Poland, and cDepartment of General andMolecular Biology and Genetics, MedicalUniversity of Silesia, Katowice, Poland

Key words: Adams-Oliver syndrome –endocrinopathy – growth – growthhormone therapy – short stature

Corresponding author: Maria A Kalina,Department of Pediatrics, PediatricEndocrinology and Diabetes,Medical University of Silesia, Ul.Medykow 16, 40-752Katowice, Poland.Tel.: +48 322023762;fax: +48 32 2071653;e-mail: majak 2001@yahoo.com

Received 24 January 2010, revised andaccepted for publication 17 May 2010

Adams-Oliver syndrome (AOS; MIM 100300),is a rare genetic condition, for which terminaltransverse limb defects (TTLD) and aplasia cutiscongenital (ACC) are the major diagnostic cri-teria (1). The syndrome was first described byForrest Adams and C. Peter Oliver in 1945 in athree-generation family with autosomal dominantinheritance with variable expressivity (2). How-ever, several studies have suggested a recessivepattern of inheritance (3–9). The wide spectrumof clinical expressions of AOS includes cardio-vascular malformations, lesions in the central ner-vous system (CNS), with various impact on thepsychomotor development, as well as impairedgrowth (1, 10–12). However, there is a lack of

data on possible underlying endocrine mechanismin the latter disturbance.

To our knowledge this is the first report ongrowth pattern accompanied by hormonal assess-ment in patients with AOS, as well as the firstdescription of a short-statured child with AOS fea-tures treated with recombinant growth hormone(GH).

Patients and methods

Three children with clinical features of AOS werefollowed in terms of growth and development forthe mean period of 3.2 years. In each case, thehypothalamic-pituitary axis was evaluated on thegrounds of basal or stimulated hormonal assays,

227

Kalina et al.

depending on clinical indications. At the firstendocrine evaluation, children were at the age of1.9 years (Patient 1), 3.6 years (Patient 2) and8.2 years (Patient 3), and did not show any puber-tal signs.

Auxologic birth data were taken retrospectively,whereas during the observational period follow-ing parameters were derived from anthropometricmeasurements: number of standard deviations (SD)for the height (hSDS), occipital-frontal circumfer-ence (OFC SD), and the weight appropriate forthe height. Besides, change of hSDS in a yearon the basis of 6-month follow-up (delta hSDS),as well as the difference between the child andmid-parental hSDS (hSDS-mpSDS) were evalu-ated. All calculations were carried out in relation tothe national auxologic charts (13). Sexual develop-ment was assessed according to the Tanner staging.

Concentrations of pituitary hormones [thyroid-stimulating hormone (TSH), luteinizing hormone(LH), follicle-stimulating hormone (FSH) and pro-lactin (PRL)], and peripheral hormones (free thy-roxine fT4, cortisol), as well as the insulin-likegrowth factor type 1 (IGF-1) were assayed in eachcase. Additionally, in Patient 1, the human chori-onic gonadotropin (HCG) test with determinationof testosterone levels was carried out according toa 5-day protocol. In Patient 3, GH was assessedin the night profile and in two provocative testswith clonidine and insulin respectively, accordingto the national protocol qualifying children for theGH therapy. All the aforementioned parameterswere assayed using chemiluminescent immuno-metric method (Immulite, Euro/DPC, Llanberis,UK). Besides, glucose profile (fasting, postpran-dial, and night glycemia) was performed in allcases. Oral glucose tolerance test was carried outin Patient 3.

Neuroimaging before and after intravenous con-trast injection was performed by means of themagnetic resonance imaging (MRI) in Patients 1and 3, and by the computed tomography (CT)in Patient 2. Neurologic examination also com-prised electroencephalograms and evaluation of thepsychomotor development by a neurologist anda psychologist. Cardiological assessment includedelectrocardiograms and echocardiography.

Karyotypes were normal in all cases.Patients’ parents gave informed consent to

participate in the diagnostic procedures and thefollow-up.

Clinical report

Patient 1

The boy was the first and the only child of young,healthy, non-consanguineous parents. In the 7thmonth of gestation oligohydramnios was visual-ized and the child was delivered at 37 weeks ofgestation by caesarean section, with Apgar score4/5/6, birth weight of 1570 g (−3.36 SD), length47 cm (−0.94 SD), OFC 28 cm (−3.71 SD), andsigns of intrauterine growth retardation (IUGR).Newborn period was complicated by bacterialsepsis and hyperbilirubinemia. Complex congen-ital defects were found at birth, including hydro-cephalus, hypertrophy of the right heart ventricledue to premature closure of the ductus arteriosus,and Peters’ anomaly in the form of hydrophtal-mos of the left eye, corneal staphyloma of theright eye and cataract. Bone defects comprisedabsence of distal phalanges 1–5 of the right hand,digits 1–5 of the left foot, and right metatarsalbones. Remaining nails were hypoplastic. Skullsutures were wide, with area of aplasia cutis mea-suring 10 cm × 10 cm over the vertex of the scalpwith an underlying bony defect. There was facialdysmorphy due to eye defects, prominent frontalsuture and midfacial hypoplasia. Other abnormal-ities included simian crease, cobbler’s chest andscoliosis.

At the age of 6 months, myoclonus followedby atypical absences and tonic seizures wereobserved. Electroencephalogram revealed parox-ysmal changes more pronounced in temporalregions, and combined pharmacotherapy was intro-duced. At the age of 7 months, due to increasingventriculomegaly, endoscopic ventriculocysternos-tomy and implantation of a ventriculoperitonealshunt were performed.

Neurological examination showed horizontalnystagmus, decreased axial muscle tone, increasedin extremities, preserved tendon reflexes anddystonic movements. Psychomotor developmentwas significantly delayed, evaluated at the ageof 19 months at the level of 1 month (Brunet-Lezine scale). MRI revealed signs of disturbedneuronal migration and segmental polymicrogyria,as well as abnormalities of midline CNS structures,including hypoplasia of the corpus callosum, mildectopy of cerebellar tonsils, and a cyst of theseptum pellucidum.

Owing to poor growth rate and hypoplasticCNS structures, the boy was submitted to furtherauxologic and endocrine assessment. At the ageof 1.9 years his body length, weight and OFCwere all below 3rd centile (76 cm; 5.79 kg;40 cm; respectively), indicating significant length

228

Clinical phenotype of Adams-Oliver syndrome

deficit (hSDS = −5.0), 4 kg of underweight forthe height, and microcephaly (OFC SDS = −7.3).The deviation from the parental height hSDS-mpSDS was significant, and was as low as −4.3SDS. During the follow-up, further slowing ofthe growth rate (delta hSDS/year = −1.0; Fig. 1)and poor weight gain were observed. Besides,cryptorchidism and inguinal hernia were found onthe left side, whereas the right testis was migrant,but easily drawn to the scrotum.

All the hormonal assays were normal andappropriate for the prepubertal period, apart fromrepeated low IGF-1 levels. Maximal basal IGF-1concentration was 20 ng/ml (<2 SD, accordingto local laboratory norms). In the HCG testappropriate testosterone response was noted, withover fivefold increment after HCG administration.No hypoglycemic incidents were detected.

Owing to numerous surgical and neurologi-cal interventions, further diagnostics for GH defi-ciency have not been undertaken yet. There wassome weight improvement after gastrostomy; how-ever, the patient needs careful follow-up of furthergrowth and development.

Patient 2

The girl was the second child of young, healthynon-consanguineous parents. Her older sister washealthy. A further pregnancy resulted in a spon-taneous abortion in the 10th week of gestation.The pregnancy of which the proband was bornwas complicated by vaginal bleeding in the secondmonth of gestation and since then the pregnancyhad been pharmacologically sustained. There wassuspicion of IUGR; however, the girl was bornby vaginal delivery at term, with the weight of3220 g (0.42 SD), length 53 cm (1.41 SD), andOFC of 32 cm (−2 SD). At the age of 2 monthsshe underwent cardiosurgical operation of the dou-ble outlet right ventricle. Due to the postoperativesecond/third degree atrioventricular block, a pace-maker and an epicardial electrode were implantedat the age of 6 months. Bone defects includedabsent right toes 3–5 and the right metatarsalbones, as well as bilateral lack of distal pha-langes 5. Remaining nails were hypoplastic. Later,one scalp defect 3 cm × 3 cm at the vertex,without underlying bone defect was noted. Dys-morphic features included microcephaly, maloc-clusion, hypothelorism, flat, wide nose base, shortneck and scoliosis. Neurological examination wasnormal. At the age of 3 years a paroxysmalepisode was observed, with abnormal electroen-cephalographic pattern without paroxysmal activ-ity. No pharmacotherapy was introduced. Brain CT

showed wide fourth ventricle and wide peristemcisterns without increased intracranial pressure.Global psychomotor and intellectual developmentwere normal (IQ = 98; Terman-Merrill scale).

At the age of 3.6 years, her height (98.5 cm;hSDS = −0.46) was within 25–50th centile range,weight appropriate for the height, but OFCremained deficient (47 cm; OFC SD = −2.44). Inthe first and the second year of the follow-upher growth was satisfactory (delta hSDS1 = 0.36and delta hSDS2 = 0.14, respectively); however,showing a slowing down trend in the recent year(delta hSDS = −0.58) (Fig. 2).

The concentration of TSH was assayed duringneurological examinations, revealing elevated val-ues. Owing to the fact that two other patients withAOS under our supervision were then suspectedfor endocrinopathies, basic hormonal parametersinfluencing growth and development, as well ascarbohydrate metabolism, were also assessed inPatient 2. The only abnormality found was subclin-ical hypothyroidism, manifesting with increasedTSH levels, along with normal FT4, low anti-thyroid antibodies, and normal thyroid ultrasoundimage. Levothyroxine treatment was introduced.At the moment the girl is euthyroid.

Patient 3

The girl was delivered at term by spontaneousvaginal labor, as the first child of young, healthy,unrelated parents. The Apgar score was 10, birthweight was 2550 g (−1.92 SD), length 50 cm(−0.24 SD), OFC 32 cm (−2 SD) and there weresigns of IUGR. The pregnancy was complicated inthe first trimester by respiratory viral infection inthe mother. The second child of the parents washealthy.

The proband was born with absent toes 2–5 ofthe right foot and a hypolastic nail of the right hal-lux. There were two areas of atrophic skin (2 cm ×3 cm and 1 cm × 2 cm, respectively) at the vertex.The skin had a texture of cutis marmorata. Dys-morphic features included microcephaly, midfacialhypoplasia, secondary prognatism with wide den-tal spacing, downslanted palpebral fissures, low-set ears, depressed nasal bridge, and broad nares.Besides, thoraco-lumbar scoliosis was observed.No cardiac defects were found.

Psychomotor development has been moderatelydelayed. The girl attends school for children withspecial needs, occasionally presenting behavioraldisturbances in the form of tantrums. No epiplepticepisodes have been reported.

At the age of 8.2 years, she was referred toan endocrinologist due to poor growth rate and

229

Kalina et al.

Fig. 1. Growth curve of Patient 1 plotted against the growth chart of healthy Polish boys. Bold, broken line indicates growth basedon retrospective data; bold continuous line indicates growth during the follow-up.

230

Clinical phenotype of Adams-Oliver syndrome

Fig. 2. Growth curve of Patient 2 plotted against the growth chart of healthy Polish girls. Bold, broken line indicates growth basedon retrospective data; bold continuous line indicates growth during the follow-up.

231

Kalina et al.

short stature. The girl presented with signifi-cant height deficit, measuring 104.2 cm (hSDS =−5.56), significantly deviating from her parents’height, with hSDS-mpSDS as low as −4.17. Herheight velocity showed a slowing down pattern(delta hSDS1 = −0.66). She weighed 15.8 kg,which reflected 1.2 kg underweight for the height.Her OFC was below 3rd centile and measured49 cm (−2.6 SD).

Neuroimaging revealed the small pituitary withborderline height for the bone and calendarage, and segmental polymicrogyria. Maximal GHconcentration was 8.1 ng/ml. Levels of IGF-1 werealso low and the maximal value was 52 ng/ml(<−2 SD). All other assayed hormones werewithin normal ranges. The bone age was delayedby 1 year according to Greulich-Pyle standards.

In the connection with the above, the girlstarted GH therapy at the age of 8.6 years. Inthe first year of therapy there was significantimprovement of height velocity (8.5 cm/year vs.3 cm/year prior to the treatment), and the changein hSDS reached positive value of as much as1.36. In the second year of therapy, growthrate stabilized, and it was estimated as much as5 cm/year, the value of delta hSDS remainingpositive (0.05) (Fig. 3). The patient did not showany signs of sexual development, despite gradualbut harmonic advancement of the bone age. Thedosage of GH was gradually increased from 0.025to 0.04 mg/kg/24 h. Apart from growth-promotingeffect, improvement of muscular strength andgross coordination was also observed during GHtherapy. No adverse events have been noted sofar. Carbohydrate parameters are checked regularlyonce a year, and both glycemia and insulinemiahave always been within normal ranges.

Discussion

Pathogenesis of AOS has not been elucidatedyet; however, it has been suggested that the con-stellation of clinical findings result from earlyembryonic vascular disruption (7, 14–19). Sev-eral gene candidates involved in limb and skulldevelopment were also investigated; however, atpresent no disease-causing gene has been identi-fied (20). In fact, AOS may manifest with widespectrum of clinical expressions, of which shortstature and undescended testes are in the scopeof the endocrinologist interest (1, 19, 21–23).Many subjects with ACC/TTLD and additionalfeatures may represent unrecognized microdele-tion or duplication syndromes (1). However, themolecular basis of these disorders remains to be

investigated, and for today they may be con-sidered as Adams-Oliver like syndromes. Thediagnosis is still based on clinical criteria (1),which were also met by patients included in ourstudy.

Growth velocity and sexual development are oneof the most important indicators of child’s health,reflecting complex interactions of environment,genetics and the endocrine system. Short stature iscaused mostly by extra-hormonal factors, includ-ing familial and constitutional conditions, systemicdisorders and chromosomal aberrations. Increas-ing number of cases, previously described as idio-pathic short stature, find explanation in molecularabnormalities. On the other hand, endocrinopathiesconstitute for less frequent causes of short stature;however, arising possibility for appropriate treat-ment with a chance for normal growth and devel-opment (24).

Another group which may exhibit poor catch-upgrowth are children born small for gestational age(SGA) and/or with signs of IUGR (25). Childrenwith AOS may also experience IUGR, as it wasdescribed in several reports (6, 7, 19, 23, 26–29).Similarly, impaired fetal growth was suspectedin all our patients, and two of them were bornSGA with signs of hypotrophy. Patients 1 and3 manifested poor height velocity from birth,whereas height of Patient 2 followed the 25–50thcentile until the age of 6, when the tendency forgrowth deceleration was observed. Short staturein AOS has been described by several authors (6,7, 23, 30); however, normal growth parametershave been recorded as well (1, 5, 8, 15). Morefrequently microcephaly is reported (1, 12, 26,27, 29), in some cases with OFC evolution tonormal in the course of time (15, 29), or evenmacrocephaly (5, 31). All our patients were bornand remained microcephalic during the follow-up.

Auxologic and hormonal deficits may also beassociated with CNS lesions, and in particular withmidline defects. The latter have been describedas markers for hypothalamic-pituitary deficiencies;hence, the raising role of neuroimaging in dif-ferential diagnosis of short stature (32–33). Suchabnormalities were found in Patient 1, who alsopresented significant growth retardation. In suchcases, from a clinical point of view, the mostessential is to exclude severe hormonal deficien-cies resulting in hypoglycemia, namely adrenocor-ticotropic hormone and GH deficiencies. In ourpatient glucose levels were normal; however, IGF-1 concentrations were low on several occasions.In such a case GH deficiency cannot be excluded.Clearly, Patient 1 suffered from complex disorders

232

Clinical phenotype of Adams-Oliver syndrome

Fig. 3. Growth curve of Patient 3 plotted against the growth chart of healthy Polish girls. Bold, broken line indicates growth basedon retrospective data; bold continuous line indicates growth during the follow-up; GH indicates initiation of GH therapy.

233

Kalina et al.

and several factors influenced his developmentaloutcome.

Patient 2 did not show any severe CNS lesions inthe CT scans, and her growth, despite the complexheart defect, was generally normal. Subclinicalhypothyroidism is rather an accidental finding inthis case. After levothyroxine had been applied,slight improvement of growth velocity within thesame centile range was noted. Recently the girlhas been reducing growth velocity, demandingfurther observation. However it is believed, thegirl’s growth should not be generally impaired,providing the euthyroid state is maintained.

The case of Patient 3 is of special interest asthe girl was diagnosed thoroughly for GH defi-ciency. Decelerating height velocity was the mainindication for such procedures. Detected GH con-centrations may be defined as partial GH defi-ciency. Although it is believed that growth defectsin developmental syndromes result mainly fromimpaired cellular growth, however, some abnor-mality in GH/IGF-1 axis may also be hypoth-esized. Broader availability of recombinant GHexpanded indications for GH therapy, and apartfrom correction of height, it may have positiveinfluence on body composition, energy expen-diture, cognitive functioning and muscle tone,as it was described among others in patientswith Prader-Willi syndrome, Noonan syndromeor Silver-Russel syndrome (34). After significantgrowth improvement in the first year, subsequentyears of GH therapy in Patient 3 might not seemas satisfactory; however, there were other benefitsderived from GH treatment, namely strengthen-ing muscle tone and improving motor coordina-tion. We have not observed any GH-related com-plications, however, issues like long-term safetyand cost-effectiveness of GH therapy in such arare disease must be taken into consideration. Thegirl’s puberty has not progressed yet, requiring fur-ther follow-up and possible dynamic evaluation forgonadotropin secretion. The MRI findings in thispatient are not characteristic for hormonal deficien-cies, as even the smaller size of the pituitary mayevolve in the course of time (35). However, con-sidering polymicrogyria, another CNS finding inthis patient, to be associated with developmen-tal delay, we support postulates of some otherauthors that neuroimaging and appropriate neuro-logical examination are necessary for the identifi-cation of AOS patients at risk (12).

Confrontation of these three patients was inten-tional. Patients 1 and 3 clearly showed short statureand poor growth velocity, which also found labo-ratory expression of low concentrations of IGF-1in both cases and additionally low levels of GH

in Patient 3. Although Patient 1 was investigatedonly partially with respect to GH deficiency, clin-ical symptoms like significantly decreased growthvelocity, hypogonadism, neonatal hyperbilirubi-naemia and midline defects were indicative of apituitary endocrinopathy. In such a case invasiveinvestigations, including GH stimulation testing,due to the young age of the patient and coexist-ing abnormalities, were unnecessary. On the otherhand, Patient 2 may be considered as a controlsubject, because the girl showed normal auxology,followed by normal laboratory markers. Present-ing her, in contrast to two other patients, providesevidence that children with AOS and associatedclinical features of endocrine disturbances, andparticularly those slowing down growth, are prob-ably to require appropriate specialist follow-up.Hence, we support the standpoint that careful clin-ical evaluation is of priority, selecting patients forfurther complex diagnostics.

Our intention was to underline the need of dif-ferential diagnosis in case of growth disturbancesin congenital syndromes. Short stature has beendescribed in several reports concerning AOS; how-ever, there is no clear information on growth veloc-ity and possible overlapping causes or correlationwith certain CNS lesions. We believe our reportadds new information on the phenotype of chil-dren with AOS, as well as on possibilities of theirmanagement. There should be an interdisciplinaryapproach to the follow-up of AOS children, withcareful monitoring of their psychomotor develop-ment, growth and puberty.

Acknowledgements

We are grateful to Krystyna Chrzanowska, MD, PhD, the Headof the Genetic Out-patient Counseling Unit in the Children’sMemorial Health Institute, Warsaw, for broadening our access toliterature references. We would also like to thank the patients andtheir parents for the kind and permissive cooperation.

Conflict of interest

Nothing to declare.

References

1. Snape KMG, Ruddy D, Zenker M et al.The spectra of clini-cal phenotypes in aplasia cutis congenital and terminal trans-verse limb defects. Am J Med Genet Part A 2009: 149A:1860–1881.

2. Adams FH, Oliver CP. Hereditary deformities in man due toarrested development. J Hered 1945: 36: 3–7.

3. Koiffmann CP, Wajntal A, Huyke BJ et al. Congenital scalpskull defects with distal limb anomalies (Adams-Oliver syn-drome – McKusick 10030): further suggestion of autosomalrecessive inheritance. Am J Med Genet 1988: 29: 263–268.

234

Clinical phenotype of Adams-Oliver syndrome

4. Klinger G, Merlob P. Adams-Oliver syndrome: autosomalrecessive inheritance and new phenotypic-anthropometricfindings. Am J Med Genet 1998: 79: 197–199.

5. Amor DJ, Leventer RJ, Hayllar S, Bankier A. Polymicr-ogyria associated with scalp and limb defects: variantof Adams-Oliver syndrome. Am J Med Genet 2000: 93:328–334.

6. Unay B, Sarici SU, Gul D et al. Adams-Oliver syndrome:further evidence for autosomal recessive inheritance. ClinDysmorphol 2001: 10: 223–225.

7. Prothero J, Nicholl R, Wilson J et al. Aplasia cutis congenita,terminal limb defects, and falciform retinal folds: confirmationof a distinct syndrome of vascular disruption. Clin Dysmorphol2007: 16: 39–41.

8. Temtamy S, Aglan MS, Ashour AM et al. Adams-Oliver syn-drome: further evidence of an autosomal recessive variant. ClinDysmorphol 2007: 16: 141–149.

9. McGoey RR, Lacassie Y. Adams-Oliver syndrome in siblingswith central nervous system findings, epilepsy, and devel-opmental delay: Refining the features of a severe autoso-mal recessive variant. Am J Med Genet Part A 2008: 146A:488–491.

10. Whitley CB, Gorlin RJ. Adams-Oliver syndrome revisited.Am J Med Genet 1991: 40: 319–326.

11. Zapata HH, Sletten LJ, Pierpont ME. Congenital cardiac mal-formations in Adams-Oliver syndrome. Clin Genet 1995: 47:80–84.

12. Papadopoulou E, Sifakis S, Raissaki M et al. Antenatal andpostnatal evidence of periventricular leukomalacia as a furtherindication of vascular disruption in Adams-Oliver syndrome.Am J Med Genet Part A 2008: 146A: 2545–2550.

13. Palczewska J, Niedzwiecka Z. Somatic development indicesin children and youth of Warsaw. Med Wieku Rozw 2001: 2(suppl. 1): 55–56, 63–64, 115–116.

14. Jaeggi E, Kind C, Morger R. Congenital scalp and skulldefects with terminal transverse limb anomalies (Adams-Oliver syndrome): Report of three additional cases. EurJ Pediatr 1990: 149: 565–566.

15. Fryns JP, Legius E, Demaerel P et al. Congenital scalp defect,distal limb reduction anomalies, right spastic hemiplegia andhypoplasia of the left arteria cerebri media. Further evidencethat interruption of early embryonic blood supply may resultin Adams-Oliver (plus) syndrome. Clin Genet 1996: 50:505–509.

16. Swartz VP, Sanatani S, Sandor GG et al. Vascular abnormal-ities in Adams-Oliver syndrome: Cause or effect? Am J MedGenet 1999: 82: 49–52.

17. Piazza AJ, Blackston D, Sola A. A case of Adams-Oliversyndrome with associated brain and pulmonary involvement:further evidence of vascular pathology? Am J Med Genet PartA 2004: 130A: 172–175.

18. Maniscalco M, Zedda A, Faraone S et al. Association ofAdams-Oliver syndrome with pulmonary arteriovenous mal-formation in the same family: a further support to thevascular hypothesis. Am J Med Genet Part A 2005: 136:269–274.

19. Patel MS, Taylor GP, Bharya S et al. Abnormal pericyterecruitment as a cause for pulmonary hypertension in

Adams-Oliver syndrome. Am J Med Genet Part A 2004:129A: 294–299.

20. Verdyck P, Blaumeiser B, Holder-Espinasse M et al. Adams-Oliver syndrome: clinical description of a four-generationfamily and exclusion of five candidate genes. Clin Genet 2006:69: 86–92.

21. Scribanu N, Temtamy SA. The syndrome of aplasia cutiscongenital with terminal, transverse defects of limbs. J Pediatr1975: 87: 79–82.

22. McMurray BR, Martin LW, St John Dignan P, et al. Hered-itary aplasia cutis congenita and associated defects. Threeinstances in one family and a survey of reported cases. ClinPediatr (Phila) 1977: 16: 610–614.

23. Fryns JP, Corbeel L, van der Berghe H. Congenital scalpdefect with distal limb reduction anomalies. Eur J Pediatr1977: 126: 289–295.

24. Oostdijk W, Grote FK, de Muinck Keizer-Schrama S et al.Diagnostic approach in children with short stature. Horm Res2009: 72: 206–217.

25. Gluckman PD, Hanson MA. The consequences of being bornsmall – an adaptive perspective. Horm Res 2006: 65 (suppl.30): 5–14.

26. Bamforth JS, Kaurah P, Byrne J et al. Adams-Oliver syn-drome: a family with extreme variability in clinical expression.Am J Med Genet 1994: 49: 393–396.

27. Orstavik KH, Stromme P, Spetalen S et al. Aplasia cutiscongenita, associated with limb, eye, and brain anomalies insibs: a variant of Adams-Oliver syndrome? Am J Med Genet1995: 59: 92–95.

28. Pousti TJ, Barlett RA. Adams-Oliver syndrome: Genetics andassociated anomalies of cutis aplasia. Plast Reconstr Surg1997: 100: 1491–1496.

29. Savarirayan R, Thompson EM, Abbott KJ et al. Cerebralcortical dysplasia and digital constriction rings in Adams-Oliver syndrome. Am J Med Genet 1999: 86: 15–19.

30. Chen H. Adams-Oliver syndrome. In: Chen H, ed. Atlasof genetic diagnosis and counseling. Totawa, New Jersey:Humana Press, 2006: 23–25.

31. Mempel M, Abeck D, Lange I et al. A wide spectrum ofclinical expression in Adams-Oliver syndrome: a report of twocases. Br J Dermatol 1999: 140: 1157–1160.

32. Coutant R, Rouleau S, Despert F et al. Growth and adultheight in GH-treated children with nonacquired GH deficiencyand idiopathic short stature: the influence of pituitary magneticresonance imaging findings. J Clin Endocrinol Metab 2001: 86:4649–4654.

33. Maghnie M, di Iorgi N, Rossi A et al. Neuroimaging ingrowth hormone deficiency. In: Ranke MB, Price DA, ReiterEO, eds. Growth hormone therapy in pediatrics – 20 years ofKIGS. Basel: Karger, 2007: 93–108.

34. Mazzanti L, Tamburrino F, Bergamaschi R et al. Develop-mental syndromes: growth hormone deficiency and treatment.Endocr Dev 2009: 14: 114–134.

35. Maghnie M, Strigazzi C, Tinelli C et al. Growth hormone(GH) deficiency (GHD) of childhood onset: reassessmentof GH status and evaluation of the predictive criteria forpermanent GHD in young adults. J Clin Endocrinol Metab1999: 84: 1324–1328.

235