Developmental Disorders of the Lymphatics

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Sunday, September 03, 2006

Atypical presentation of Prader-Willi syndrome with Klinefelter (XXY karytype) and craniosynostosis

Atypical presentation of Prader-Willi syndrome with Klinefelter (XXY karytype) and craniosynostosis

Arq. Neuro-Psiquiatr. vol.64 no.2a São Paulo June 2006

Daniel R. CarvalhoI; Clovis S. TradII; João M. Pina-NetoIII

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Ribeirão Preto SP, Brazil IMédico Residente do Serviço de Genética Médica IIProfessor Responsável pelo Centro de Ciências das Imagens e Física Médica IIIProfessor Associado do Departamento de Genética


Prader-Willi syndrome is a mental retardation genetic disorder also characterized by hypogonadism, hyperphagia and obesity. We report on a four-years-old boy, born to consanguineous parents, with uncommon co-occurrence of Prader-Willi syndrome, 47,XXY karyotype (Klinefelter syndrome) and coronal craniosynostosis. These are different unrelated conditions and it was not described before in the same patient to the best of our knowledge.

Key words: XXY karyotype, Prader-Willi syndrome, Klinefelter syndrome, craniosynostosis.

Prader-Willi syndrome (PWS) is a genetic disorder with prevalence of 1/10,000 to 1/25,000 characterized by hypotonia in early infancy, hyperfagia, obesity and mental retardation in childhood associated with hypogonadism and short stature1. Klinefelter syndrome (KS) is the most common sex chromosome disorder (1/500 male newborn) that usually is not easily clinical perceived during childhood and curses without developmental delay, but small testicles and infertility is a frequent problem in post-pubertal age2. Several patients with both PWS and KS have been documented. The last reports revealed distinct genetic mechanisms of the two conditions that reinforce the coincidental association of (1) uniparental maternal heterodisomy of chromosome 15 and paternal X-Y chromosome non-disjunction3 or (2) paternally inherited microdeletion of chromosome 15 and maternal X-X inherited meiosis 1 non-disjunction4,5.

Butler et al. solicited more reports of affected PWS patients with atypical presentation3. We describe another case of this co-occurrence of PWS and KS with the additional aspect of coronal craniosynostosis.


We have evaluated a four-years-old boy since his first year of life. He is the second child of a young consanguineous couple (F=1/16) and his sister had an isolated cleft lip. He was born after an uneventful pregnancy and vaginal delivery with a birth weight of 2,566 g and birth length of 46 cm.

At age 9 months, his length was 71 cm (25th percentile), his weight was 7.8 kg (3rd percentile), he had an OFC of 43.5 cm (between 3rd and 10th percentile), hypotonia, brachycephaly with pronounced temporal bossing, small penis (length of 2.1 cm, below 10th percentile) and cryptorquidia with hypoplastic scrotum. Peripheral blood cytogenetic analysis (GTG) at 550 band level resolution showed a 47,XXY karyotype. Bone reconstruction CT scan revealed an early closure of the anterior and posterior coronal sutures, but surgical intervention was not necessary (Figs 1, 2 and 3). Clinical observation noted obesity, hyperphagia and developmental delay without any sign of increased intracranial pressure. He sat at 18 months, crawled at 22 months and a broad-based flat-footed gait was observed at 3 years of age. At 4 years and 2 months of age, he had skin picking and was able to pronounce few words even after speech therapy. At this age, his length was 89 cm (below 3rd percentile), his weight was 18 kg (75th percentile), and he had an OFC of 48.5 cm (3rd percentile). Also observed was a narrow bifrontal diameter, epicanthic folds, almond shaped oblique palpebral fissures, esotropia, cupid arch upper lip with sticky saliva, marked truncal obesity and small hands and feet.

A methylation analysis was done by Southern blotting using a KB17 probe to the 15q11-13 region that confirmed the missing paternal 0.9 Kb band compatible with PWS1,6 (Fig 3). Unfortunately, his mother died in an accident before the last exam. His grandmother became his legal guardian because his father moved away. It was not possible to investigate the parental origin of the genetic abnormality mechanism.


Craniosynostosis is considered a premature fusion of calvarial sutures, often associated with neurological manifestations or limb and craniofacial abnormalities. It can be an isolated clinical problem or part of diverse known syndromes7. The overall incidence for all forms of craniosynostosis is 1/2,000-1/2,500 live births7.

Considering the consanguinity and the absence of limbs anomalies, we propose that non-surgical premature coronal closure may be a recessive, non-syndromic, form of craniosynostosis and also an incidental co-occurrence in this patient.

The clinical presentation of this case must be distinguished from non-synostotic posterior plagiocephaly (positional molding) secondary to hypotonia or sleeping in the supine position during the early perinatal period because anterior and posterior coronal sutures are involved bilaterally8.

Usually with the XXY boys, abnormalities are not apparent during childhood, except for possible mild language delays. Additionally, some authors reported that small penis and testes, or underdevelopment of external genitalia, are possible clues to precocious detection of Klinefelter children9, but these signs are found in few patients.

We believe that any uncommon aspect in XXY children – like hypotonia, hyperphagia, or the hypogonadism detected in our patient – should raise suspicion for evaluation of another associated condition. It would promote the early diagnosis that is essential for adequate management of PWS children.


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2. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998;158:1309-1314. [
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3. Butler MG, Hedges LK, Rogan PK, Seip JR, Cassidy SB, Moeschler JB. Klinefelter and trisomy X syndromes in patients with Prader-Willi syndrome and uniparental maternal disomy of chromosome 15: a coincidence? Am J Med Genet 1997;72:111-114. [
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6. Glenn CC, Saitoh S, Jong MT, et al. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet. 1996;58:335-346.
7. Cohen MM Jr., MacLean RE. Craniosynostosis: diagnosis, evaluation and management, 2nd edition. New York: Oxford University Press, 2000.
8. Ellenbogen RG, Gruss JS, Cunningham ML. Update on craniofacial surgery: the differential diagnosis of lambdoid synostosis/posterior plagiocephaly. Clin Neurosurg 2000;47:303-318. [
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9. Caldweel PD, Smith DW. The XXY (Klinefelter’s) syndrome in childhood: detection and treatment. J Pediatr 1972; 80:250-258.

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