Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Sunday, September 24, 2006

Prognosis, with evaluation of general biochemistry, of liver disease in LCS1/Aagenaes syndrome

Prognosis, with evaluation of general biochemistry, of liver disease in lymphoedema cholestasis syndrome 1 (LCS1/Aagenaes syndrome).

Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.


To investigate the prognosis of liver disease in Aagenaes syndrome (lymphoedema cholestasis syndrome 1 (LCS1)), which is an autosomal recessive inherited syndrome consisting of neonatal cholestasis with intermittent cholestatic episodes in childhood into adulthood and development of lymphoedema. Forty Norwegian patients are known to have this condition, 25 of whom are alive. A clinical description of the liver disease is supplied with a case-control study.


In this paper we review the course of the liver disease in the Norwegian cohort of patients and present results from a case-control study in the patients above 10 years of age. The case-control study was performed on 15 patients without clinical cholestasis (itching and sometimes jaundice) at the time of the study. An evaluation of 11 patients above 15 years of age without chronic biochemical cholestasis (increased alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and/or serum bile acids) was also carried out. For each patient one randomly identified control person was included (15 in one study, 11 in the other).


Cirrhosis with either transplantation or death in infancy or early childhood occurred in six patients; slowly developing cirrhosis occurred in three patients. Two patients may be in the process of developing cirrhosis. Significantly increased ALP and GGT levels were found in patients with normal liver biochemistry in the preceding years when compared with the case control group. Additionally, albumin was found to be lower in older patients.


Compared with that for other types of hereditary neonatal cholestasis, patients with LCS1 have a relatively good prognosis. More than 50% can expect a normal life span.

PMID: 16635916 [PubMed - indexed for MEDLINE]

Sunday, September 17, 2006

Kasabach-Merritt syndrome associated with giant liver hemangioma

Kasabach-Merritt syndrome associated with giant liver hemangioma: the effect of combined therapy with danaparoid sodium and tranexamic acid

E-case haematologica 2005;90:(ECR)29

Yasuo Ontachi,1 Hidesaku Asakura,1 Mika Omote,2 Tomotaka Yoshida,2 Osamu Matsui ,3 Shinji Nakao1

1Department of Internal Medicine (III), Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8641, JAPAN; 2The department of Laboratory, Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa, Ishikawa 920-8641, JAPAN; 3Department of Radiology, Kanazawa University School of Medicine, Kanazawa, Ishikawa, 920-8641, JAPAN

CorrespondenceYasuo Ontachi, Department of Internal Medicine (III), Kanazawa University School of Medicine, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, JAPAN. Fax: +81-76-234-4252 E-mail:


In patients with Kasabach-Merritt syndrome (KMS), local activation of coagulation commonly results in disseminated intravascular coagulation (DIC). Progress of DIC is associated with 30âÄì40% mortality as a result of uncontrollable hemorrhage. A 39-year-old woman with an enlarging giant liver hemangioma was diagnosed as having KMS with DIC. To control the hemorrhagic diathesis, we commenced combination therapy for DIC with danaparoid (1,250 Ux2/day, intravenously (IV)) and tranexamic acid (0.5 g x 3/day, peros (PO). Rapid improvement of the bleeding tendency and coagulopathy occurred in response to this treatment âÄì that is, DIC was controlled without removing the giant hemangioma. The therapy did not restrict the behavior of the patient by continuous drip and angiography could be performed without bleeding. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis.

Kasabach-Merritt syndrome (KMS) was first reported in 1940 in a neonate as the association of thrombocytopenic purpura and a rapidly enlarging capillary hemangiom.1 Not all hemangiomas in this syndrome are cutaneous, and those associated with a more severe phenotype are often visceral. The incidence of hepatic hemangioma in KMS is reported to be about 2%.2 In patients with this syndrome, local activation of coagulation commonly results in disseminated intravascular coagulation (DIC).3,4 The incidence of clinically overt DIC is 25% among patients with giant hemangiom.1,3 However, neither the site nor the size of the hemangioma appears to reliably predict the subsequent development of KMS, which has been associated with 30âÄì40 % mortality as a result of uncontrollable hemorrhage.5 This report describes a case of chronic DIC associated with KMS and the management with a combination of danaparoid and antifibrinolytics.

Case report

A 39-year old woman was admitted to our hospital in September 2001 due to abdominal swelling. She had previously undergone surgical ligation of the hepatic artery for giant liver hemangioma in 1994. Although this had resulted in temporary remission, abdominal enlargement had gradually recurred. Physical examination on admission revealed several ecchymoses on the upper extremities and hepatomegaly. Coagulation studies demonstrated the following: platelet count, 90x109/L (normal range: 150-300x109/L); prothrombin time (PT), 12.5 sec (normal range: 9.4-11.1 sec); activated partial thromboplastin time (APTT), 32.6 sec (normal range: 27.5-42.1 sec); fibrinogen (Fbg), 100 mg/dl (normal range: 206-369 mg/dL); fibrin/fibrinogen degradation product (FDP), 37.8 µg/mL (normal range: <5>


DIC is characterized by the widespread activation of coagulation, which results in the intravascular formation of fibrin. Although it is a severe clinical condition that involves considerable activation of both coagulation and fibrinolysis in the circulating blood, the degree to which the fibrinolytic system is activated in DIC varies according to the underlying disease.3,6,7 In this case of DIC associated with KMS, the data of PIC (above 4 m g/ml) support the existence of activation of fibrinolysis.7 The cornerstone of the management of DIC is treatment of the underlying disorder. The replacement of consumed clotting factors with fresh-frozen plasma or platelet concentrate is only indicated when to prevent bleeding.3 It is known that KMS is a cause of DIC and a strong local activation and local consumption coagulopathy has been reported in hemangioma.4 Elimination of the tumor is needed to control DIC with KMS. However, no treatment modality has been established as consistently effective.5 Radiotherapy is rarely considered as first-line therapy because of its known late effects on tumor growth and secondary malignancies. However, it is non-invasive and can be used in extremis as a last resort and has occasionally been used as first-line therapy for small inaccessible lesions.5,8 It is important to suppress the activated coagulation factor for control of DIC. An oral anticoagulant that can inhibit the activated coagulation factor is not yet commercially available. Warfarin is the only oral anticoagulant at present. There were some previous studies that warfarin treatment in chronic DIC associated with aneurysm was effective.9 Although we discussed possible warfarin treatment for this patient, we rejected warfarin treatment for two reasons. One reason is that its action is only inhibition of production of vitamin K dependent coagulation factor without suppression of activated coagulation factors, and another is that this patient had mild liver dysfunction due to the giant hemangioma.

At present, heparin is commonly used in patients with DIC, being administered in relatively low dosse.3 Low dose heparin has also been used in patients with KMS; however, evidence for its benefit has never been established. As KMS and large aortic aneurysm may both result in local activation of coagulation, coagulopathy in each condition is considered to be similar. Cummins et al. reported that long-term treatment with low molecular weight heparin (LMWH) could provide good symptomatic control of chronic DIC associated with abdominal aortic aneurysm.10 We therefore hypothesized that danaparoid, a kind of heparinoid, might also be able to control DIC occurring in KMS. Danaparoid is a heparinoid which is distinct from unfractionated heparin (UFH) and LMWH.11,12,13 Danaparoid has a longer half life of 20 hours and has a high anti-Xa/anti-IIa ratio (>20 as compared to 1 for heparin and 2 for LMWH). Moreover, as danaparoid also inhibits platelet adherence to a much lesser extent than UFH, its effect on bleeding is less marked.14 In Japan, one double-blind clinical trial in patients with DIC has shown danaparoid to be equivalent to UFH.12 In the present patient, danaparoid was selected for the reason, that is could be injected by bolus and had little risk of hemorrhagic side effects compared with other therapies. Tranexamic acid has been proposed as a hemostatic agent in many clinical conditions characterized by excessive bleeding, but the use of this agent in patients with DIC is generally not recommended.3 Kario et al. described that monitoring of the TAT/PIC ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulant and antifibrinolytic agents.15 With regard to this patient, we decided to use the anticoagulant since the level of TAT was elevated. Rodeghiero et al. reported 268 consecutive patients with acute promyelocytic leukemia.16 Patients were separated into three groups (treated with heparin, with antifibrinolytics, and with supportive therapy alone), and no significant difference was detected between these three groups in terms of overall incidence of early hemorrhagic death.16 Recently, in a tissue factor induced rat DIC model, we demonstrated that tranexamic acid suppressed the elevation in D-dimer levels and it increased organ dysfunction.17 It is considered that inhibition of fibrinolysis using tranexamic acid might cause thrombin formation. On the other hand, a case was reported of a patient with aneurysm in whom hemorrhage stopped abruptly upon the administration of tranexamic acid.18 Moreover, tranexamic acid has also been reported to be efficacious in the treatment of severe KMS in the newborn.19 In the present case, the bleeding tendency improved during the combination therapy described above. When this therapy was transiently discontinued, coagulopathy deteriorated. In this case, from the viewpoint of the characteristics of DIC, danaparoid was useful for inhibiting the activation of coagulation and preventing thrombotic complications. In contrast, tranexamic acid was useful for controlling hemorrhage. In summary, combined therapy with danaparoid (IV) and tranexamic acid (PO) enabled control of the bleeding tendency, and angiography could be performed without limitations in the present patient. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis, in which control of bleeding is required without restricting the behavior of patients by needing continuous drip.


1) Kasabach HHM, Merritt KK. Capillary hemangioma with extensive purpura. Report of a case. Am J Dis Child 1940; 59: 1063-70.2) Iqbal N, Saleem A. Hepatic hemangioma. Tex Med 1997; 93: 48-50.3) Levi M, ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999; 19: 586-92.4) Antovic J, Bakic M, Milicevic R, Gojkovic G, Blomback M. Activation of the coagulation system occurs within rather than outside cutaneous haemangiomas. Acta Paediatr 2001; 90: 1137-40.5) Hall GW. Kasabach-Merritt syndrome: pathogenesis and management. Br J Haematol 2001; 112: 851-62.6) Takahashi H, Tatewaki W, Wada K, Hanano M, Shibata A. Thrombin vs. plasmin generation in disseminated intravascular coagulation associated with various underlying disorders. Am J Hematol 1990; 33: 90-5.7) Asakura H, Jokaji H, Saito M, Uotani C, Kumabashiri I, Morishita E,et al. Study of the balance between coagulation and fibrinolysis in disseminated intravascular coagulation using molecular markers. Blood Coagul Fibrinolysis 1994; 5: 829-32.8) Ogino I, Torikai K, Kobayashi S, Aida N, Hata M, Kigasawa H. Radiation therapy for life- or function- threatening infant hemangioma. Radiology 2001; 218: 834-9.9) Micallef-Eynaud PD, Ludlam CA. Aortic aneurysms and consumptive coagulopathy. Blood Coagul Fibrinolysis 1991; 2: 477-81.10) Cummins D, Segal H, Hunt BJ, Awad R, Maddox A. Chronic disseminated intravascular coagulation after surgery for abdominal aortic aneurysm: clinical and haemostatic response to dalteparin. Br J Haematol 2001; 113; 658-60.11) Bradbrook ID, Magnani HN, Moelker HCT, Morrison PJ, Robinson J, Rogers HJ, et al. Org 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man. Br J Clin Pharmac 1987; 23: 667-75.12) Ibbotson T, Perry CM. Danaparoid: a review of its use in thromboembolic and coagulation disorders. Drugs 2002; 62: 2283-314.13) De Boer A, Danhof M, Cohen AF, Magnani HN, Breimer DD. Interaction study between Org 10172, a low molecular weight heparinoid, and acetylsalicylic acid in healthy male volunteers. Thromb Haemost 1991; 66: 202-7.14) Meuleman DG, Hobbelen PMJ, van Dedem G, Moelker HCT. A novel antithrombotic heparinoid (Org 10172) devoid of bleeding enhancing capacity: a survey of its pharmacological properties in experimental animal models. Thromb Res 1982; 27: 353-63.15) Kario K, Matsuo T, Kodama K, Matsuo M, Yamamoto K, Kobayashi H. Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio. Haemostasis 1992; 22:179-86.16) Rodeghiero F, Avvisati G, Castaman G, Barbui T, Mandelli F. Early deaths and anti-hemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990; 75: 2112-7.17) Asakura H, Sano Y, Yamazaki M, Morishita E, Miyamoto K, Nakao S. Role of fibrinolysis in tissue-factor-induced disseminated intravascular coagulation in rats - an effect of tranexamic acid. Haematologica 2004; 89: 757-8.18) Takada A, Takada Y, Mori T, Sakaguchi S. Prevention of severe bleeding by tranexamic acid in a patient with disseminated intravascular coagulation Thromb Res 1990; 58: 101-8.19) Hanna BD, Bernstein M. Tranexamic acid in the treatment of Kasabach-Merritt syndrome in infants. The Am J Pediatric Hematol Oncol 1989; 11: 191-5.


Sunday, September 10, 2006

Kimura Disease - Eosinophilic lymphogranuloma

Kimura Disease - Eosinophilic lymphogranuloma

* * * *

D I S E A S E : Kimura disease

Orphanet number: ORPHA482

Synonym(s): Eosinophilic lymphogranuloma

Kimura's disease, a rare entity in the West but endemic in Asia, manifests as solitary or multiple subcutaneous nodules, primarily located in the cervical region. They are often accompanied by local adenopathies and/or salivary gland hypertrophy. Histologically, the lesions are characterized by hyperplastic lymphoid tissue, an inflammatory infiltrate rich in eosinophils and a proliferation of postcapillary venules. Hypereosinophilia in the blood and elevated levels of circulating IgE are found. A nephrotic syndrome must be systematically sought. The etiology of this chronic inflammatory disease is unknown. An aberrant immune reaction to an unknown antigenic stimulus has been suggested. Treatment consists of surgical excision of the lesion(s) and corticotherapy is prescribed for relapsing forms and when renal involvement is present. The prognosis is good and no malignant transformation has ever been observed. Other drug classes have been tried with some success. *Authors: Dr C. Larroche, Prof O. Blétry (February 2005)*.


* * * *

What is Kimura's disease?

QuestionMy nine-year-old son has got Kimura's disease, but I have been unable to find any thing on the Internet about it. What is it?


Kimura's disease is a condition that causes non-cancerous tumours (or lumps) to develop in the head and neck region. Lymph glands may also be enlarged and there may be increased numbers of eosinophils (a type of white blood cell) in the bloodstream. Kimura's disease is very rare in Europe but is frequently diagnosed in Asian countries and in immigrants from these countries. The cause of the disease isn't clear, although one theory is that an allergen (as yet unidentified) stimulates the body to produce inflammation in certain tissues which results in the appearance of tumours and enlarged glands.There is no consensus on the best treatment for the disease. Sometimes the lumps are removed surgically; in other cases drug treatments designed to affect the immune system (for example, cyclosporin) are used; even radiotherapy and laser treatment have been tried.As Kimura's disease is so rare in Europe I don't know whether there are any other families in the UK affected by the condition but if you wanted to find out if there are, you could contact an organisation called Contact A Family. This is a UK charity that helps families who care for children with any disability or special need. They also provide information about rare disorders and if they know of any other family coping with Kimura's disease they would be able to put you in touch with them if you wished. You can telephone the Contact A Family Parent Advisers on 020 7383 3555.

Yours sincerely

The NetDoctor Medical Team

* * * *

Kimura Disease: A Clinicopathologic Study of 21 Cases.

Original Article

American Journal of Surgical Pathology. 28(4):505-513, April 2004.Chen, Hong MD *; Thompson, Lester D. R MD +; Aguilera, Nadine S. Ives MD *; Abbondanzo, Susan L MD *


Kimura disease is a rare form of chronic inflammatory disorder involving subcutaneous tissue, predominantly in the head and neck region and frequently associated with regional lymphadenopathy and/or salivary gland involvement. This condition has a predilection for males of Asian descent and may clinically simulate a neoplasm. Kimura disease is sometimes confused with angiolymphoid hyperplasia with eosinophilia, which occurs in the superficial skin of the head and neck region. Although sporadic cases have been reported in non-Asians, there is no large, comprehensive study of Kimura disease in the United States. We report 21 cases with nodal involvement that, histologically, are consistent with Kimura disease. There were 18 males and 3 females (male/female ratio 6:1), 8 to 64 years of age (mean, 32 years), and included 7 Caucasians, 6 Blacks, 6 Asians, 1 Hispanic, and 1 Arabic. Anatomic sites of involvement included posterior auricular (n = 10), cervical (n = 6), inguinal (n = 3), and epitrochlear (n = 2) lymph nodes, with two patients having associated salivary gland involvement. Most (n = 16) cases had peripheral blood eosinophilia. Consistent histologic features were follicular hyperplasia, eosinophilic infiltrates, and proliferation of postcapillary venules.

Follow-up data on 18 patients revealed that 13 were alive without disease (3 had recurrence), mean follow-up, 10.9 years; 4 were alive with disease (2 had a recurrence), mean follow-up, 8.8 years; and 1 died with disease (12.7 years). Kimura disease has been described more often in Asians, but it does occur in non-Asians with a similar clinicopathologic presentation. It is a distinctive entity with no known etiology. Kimura disease has characteristic histologic features that are important to recognize and can be used to differentiate it from hypersensitivity and drug reactions and infections.

(C) 2004 Lippincott Williams & Wilkins, Inc.

* * * *

See Also:

Kimura Disease - eMedicine

* * * *

Kimura Diease

Kimura disease (KD) was initially described in 1937, in the Chinese literature, by Kimm and Szeto1 as an “eosinophilic hyperplastic lymphogranuloma” and it became known as KD after its publication by Kimura et al.2 of similar cases in Japan under the title “Atypical granulation associated with hyperplastic abnormalities in the lymphoid tissue.” It is a chronic inflammatory disease involving the dermis and subcutaneous tissue characterized by one or multiple nodules or unpainful masses. It occurs predominantly as a unilateral manifestation in the head and neck and it is frequently associated with regional lymphadenopathy with or without involvement of salivary glands.3 Histopathologically, this condition is characterized by a lymphocytic inflammatory infiltrate, forming lymphoid follicles interspersed with aggregates of eosinophils and variable fibrosis in a richly vascular stroma. The pathophysiology of KD remains unknown, although allergic reaction, trauma and autoimmune process have been implicated as triggering factors.3,4

KD is a rare inflammatory disorder of unknown origin. Most of patients are male and oriental young adults. The prevalence in patients of other ethnicities is considered low. The disease is characterized by a triad of unpainful subcutaneous masses in the head and neck, eosinophilia in the peripheral blood and in tissues, and marked increase in serum levels of immunoglobulin E (IgE).16,17

At physical examination, patients with KD present one or more subcutaneous masses in the head and neck, accompanied by satellite adenomegalies and/or increased volume of salivary glands, especially the parotid and submaxillary glands (Figure 1). The lesions are firm at palpation, not painful and progressively increase in size with some of them reaching a diameter between 3 and 10 cm. There is a marked predominance of male patients; the male/female ratio is 2:1; and the onset of the disease occurs mostly in the third decade of life.18,19 Kung et al.3 studied 21 patients distributed as 18 men and 3 women, and they observed that the age of onset of lesions ranged from 7 to 50 years, with a mean age of 28 years. Such patients frequently reported pruritus in the overlying skin. In this study, most of the lesions were in the regions of head and neck; seven cases also presented involvement of the parotid gland. Lesions in other areas were also described such as the inguinal area, upper limbs and chest wall.3

Although KD pathogenesis remains unknown, it is considered nowadays an allergic disease and it seems to be a systemic immunological disorder. Eosinophilia and increased serum IgE levels make KD be considered a CD4(+) T helper 2 (Th2) allergic reaction. Th2 cells would produce interleukins (IL) IL-4, IL-5 and IL-13, which, in turn, would act in B cells favoring the production of antigen-specific IgE. Th2 cell proliferation and the overexpression of cytokines would play an essential role in the development of the disease.16,20

The histopathological changes in KD consist of a massive, nodular, diffuse and mixed inflammatory infiltrate composed mainly of lymphocytes and eosinophils, occupying all the extension of reticular dermis, subcutaneous tissue and, sometimes, the muscle fascia and the skeletal muscle (Figure 2). The inflammatory infiltrate is poorly circumscribed and contains numerous lymphoid follicles; infiltration of adjacent salivary glands may also occur.13,15 Lymphoid follicles are hyperplastic and contain prominent germination centers (Figure 3). Eosinophilic infiltration may occur occasionally with areas of necrosis (Figure 4). Although plasma cells and histiocytes are present, no epithelioid cells, multinucleated giant cells or granulomas are seen.3,10 Fibroplasia is seen in the subcutaneous tissue and around the lesion. Fibrosis can be sometimes observed as septa. Fibroplasia cellularity varies and tends to hyalinization of older lesions.13,21

The lesions are markedly of vascular type; capillaries are numerous and their endothelium is prominent and with no cytological atypias.13,21 Small arteries present hyperplasia or fibrosis of tunica intima and tunica muscularis. Large caliber arteries are rarely seen. Older lesions show more pronounced fibrosis, less active lymphoid follicles, less intense inflammatory infiltrate and a relatively less exuberant vascular component.13,15,21

Due to KD benign nature, treatment may range from observation and follow-up of mild and asymptomatic cases to conservative surgical excision, although lesions sometimes tend to recur. Other therapeutic options less commonly used include intralesional corticosteroids, cyclosporine, pentoxiphylline and radiotherapy.22-27

An. Bras. Dermatol. vol.81 no.2 Rio de Janeiro Mar./Apr. 2006

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.


Pina-Neto JM, Ferraz VE, de Molfetta GA, Buxton J, Richards S, Malcolm S. Clinical-neurologic, cytogenetic and molecular aspects of the Prader-Willi and Angelman syndromes. Arq Neuropsiquiatr 1997;55: 199-208. [ Medline ] [ Lilacs ]
2. Smyth CM, Bremner WJ. Klinefelter syndrome. Arch Intern Med 1998;158:1309-1314. [
Medline ]
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. [
Medline ]
4. Geffroy S, Evrard V, Taufour D, Vanderbecken S, de Martinville B. Further example of a patient with Prader-Willi and Klinefelter syndromes of different parental origins. Am J Med Genet 1998;80:286-287. [
Medline ]
5. Nowaczyk MJ, Zeesman S, Kam A, Taylor SA, Carter RF, Whelan DT. Boy with 47,XXY,del(15)(q11.2q13) karyotype and Prader-Willi syndrome: a new case and review of the literature. Am J Med Genet 2004; 125A:73-76.
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. [
Medline ]
9. Caldweel PD, Smith DW. The XXY (Klinefelter’s) syndrome in childhood: detection and treatment. J Pediatr 1972; 80:250-258.

SciElo Brazil