A 49-year-old Caucasian man was referred to our clinic because of multiple wart-like skin changes on his fingers, scrotum and perianal region, which had developed over a period of 40 years (). While the skin changes on the fingers were papules, the changes on the scrotum had coalesced into plaques. Nd:YAG laser therapy had repeatedly been performed for treatment of perianal warts and those in the right groin. Furthermore, the patient suffered from chronic scrotal lymphoedema with waxing and waning lymphorrhagia for 40 years (). The patient underwent heart surgery and inguinal hernia surgery 40 years before. Pertinent information on his heart disease was not available. Otherwise, his medical history was unremarkable. The patient had longstanding learning difficulties, and he had attended a school for children with special needs. He did not reach graduation and was currently working as a driver. He was divorced and had no children. The patient had two brothers and three sisters (one sibling died of a stroke). None of the siblings nor his deceased parents suffered from any known congenital disease.
Figure 1 (A) Multiple hyperkeratotic, verruciform tumours on different aspects of the hands and periungually. The scrotum is verrucous. Penis and scrotum are oedematous. (B) The scrotum is verrucous, the penis is lymphoedematous. Scar tissue after Nd:YAG (more ...)
Besides the warty skin changes, clinical examination showed several distinctive features: short stature (165 cm, <3rd centile), webbed neck, pectus excavatum, clubbing of the fingers and striking facial dysmorphism ().
The patient at the age of 49 years. Note the low frontal hairline, downslanting palpebral fissures, pale blue iris, broad nose, flat philtrum, and prominent nasolabial folds. The ears are low set and retroverted with a thick helix.
The warty skin changes developed at the age of 9 years and since then had always been present. Multiple viral warts can be caused by immunosuppressive illnesses but also immunosuppressive drugs, as well as hereditary diseases causing immunodeficiency. In this case, an underlying hereditary disease or a condition associated with immunosuppression, such as HIV infection, should be excluded. Inherited diseases with multiple warts are Heck’s disease, epidermodysplasia verruciformis (EV) and WHIM (warts, hypergammaglobulinaemia, infections, myelokathexis) and WILD (warts, immunodeficiency, lymphoedema, dysplasia) syndromes. Heck’s disease is mainly prevalent in New Mexico, USA, and presents with oral warts. EV occurs at birth or shortly after with pityriasis versicolor-like warts on the integument or verruciform lesions on light exposed areas and extremities. Mucosal sites are not affected. WHIM syndrome can be caused by mutations of the chemokine receptor gene CXCR4. In WILD syndrome, lymphoedema is located on both legs and the distribution of the warts is far more extensive.
Laboratory investigations focused primarily on the wart-like skin changes and showed mild elevation of white blood cell counts (WBC 11.94×109/l), haemoglobin (17.2 g/dl) and haematocrit (49%). Differential blood analyses revealed mild neutrophilic and monocytic leucocytosis. White blood cell subpopulation analyses showed an increased monocyte subpopulation with elevated CD16+ (9.612×109/l; normal value 1.8–8.6) and CD14+ cells (1.266×109/l; normal value 0.24–1). Serological analyses excluded syphilis, viral hepatitis and HIV. Serum electrophoresis did not show any abnormalities.
Chronic localised lymphoedemas are mainly secondary in nature (eg. postsurgical or due to filariasis). If localised lymphoedema presents early in life or is otherwise unexplained, primary lymphoedema should be considered.1–3
The most common form of primary lymphoedema is sporadic lymphoedema. Nonne-Milroy’s disease, the best known congenital form of primary lymphoedema, is caused by mutations in the vascular endothelial growth factor receptor 3 (VEGF-R3). Furthermore, lymphoedemas are found in Meige’s disease (late onset) and lymphoedema–distichiasis syndrome, both typically presenting with pitting oedema that is commonly limited to the legs. A large number of chromosomal disorders severely disturb lymphatic function. Turner’s syndrome may contribute to lymphoedema even in adults, but as only women are affected, this did not pertain to our patient. Noonan syndrome and the phenotypically overlapping cardio-facial-cutaneous syndrome, both related to components of the RAS-RAF-ERK pathway, are characterised by facial dysmorphism and short stature. Another heritable disorder that had to be considered is autosomal recessive Hennekam’s syndrome with facial dysmorphisms as a consequence of jugular lymphatic obstruction.2
However, lymphoedema is also found in association with several other inherited diseases ().
Multiple skin biopsies were taken from the scrotum () and fingers to exclude squamous cell carcinoma.
Figure 3 (A) Histology of the scrotum showing hyperkeratosis, hypergranulosis and acanthosis of the epidermis. Ectatic vessels with regular endothelium are seen in the upper and deep dermis, and white fluid with some erythrocytes is visible in the lumen (more ...)
Biopsies of the finger lesions showed acanthosis, papillomatosis and hyperkeratosis of the epidermis (images not shown). A few mitoses were detected, but no signs of malignancy. The result was compatible with verruca vulgaris. Human papilloma virus (HPV) subclassification showed HPV59, which is a high risk HPV for cancer development.
Skin biopsy obtained from the scrotum showed hyperkeratosis, hypergranulosis and acanthosis. Ectatic vessels with thin, regular endothelium were found in the upper layer of the dermis (). Ectatic vessels were also apparent in the deeper dermis. Intraluminally, a light fluid with only a few erythrocytes was found. These histological findings can be detected in angiokeratoma, late stages of lymphangiectases, and superficial lymphatic malformations.4–6
Since angiokeratoma was considered, the patient was referred to the department of ophthalmology. Lysosomal storage defects, such as Fabry’s disease or Kanzaki disease, may present with multiple angiokeratomas (angiokeratoma corporis diffusum) and ophthalmological changes, eg, coloboma (Fabry’s disease) or dilated vessels with corkscrew-like tortuosity in the fundi (Kanzaki disease). The clinical findings in Kanzaki disease are quite variable and localised lymphoedema has been described in previous reports.
The patient had an unusual mixed episcleral and conjunctival vessel tortuosity and ectasia with prominent limbal arcades and surrounding feeder vessels in the inferior hemisphere. These were accompanied by punctate bleedings resembling telangiectasia (). The fundus showed mild hypopigmentation of the retinal pigment epithelial cells, but no peripheral signs of retinal dystrophy or coloboma. There was pronounced disk excavation suspicious for glaucomatous optic atrophy; however, the intraocular pressure was normal. In conclusion, no signs of lysosomal storage disease were found.
Unusual mixed episcleral and conjunctival vessel tortuosity and ectasia with prominent limbal arcades and surrounding feeder vessels in the inferior hemisphere. These were accompanied by punctate bleedings resembling telangiectasia.
As an underlying hereditary disease was still considered and because of the dysmorphic signs, the patient was referred to the department of human genetics.
Apart from the findings established before, the patient showed a strikingly small stature (<3rd centile), poor mental abilities, a history of congenital heart disease, and the following signs: low frontal and posterior hairline, downslanting palpebral fissures, pale blue iris, broad nose, flat philtrum, prominent nasolabial folds, and a high arched palate. His ears were low set and retroverted with a thick helix (). These signs had been obvious since early childhood (). Furthermore, the patient showed a pterygium colli and pectus excavatum.
The patient at ages 6, 9 and 15 years. Note the prominent forehead, downward slanting palpebral fissures and low set ears.
The clinical picture of short stature, mild developmental delay in childhood, congenital heart disease with localised lymphoedema and the facial features described above were considered typical of Noonan syndrome (). Molecular genetic analyses should be performed to confirm the clinical diagnosis.
Table 1 Diagnostic criteria for the Noonan syndrome:19 Noonan syndrome can be diagnosed if 1A + 2-6A or 1A + 2 × 2-6B or 1B + 2× 2-6A or 1B + 3× 2-6B are present
Molecular genetic studies revealed a heterozygous mutation (c.215C>G; p.A72G) in the PTPN11 gene locus which encodes the non-receptor protein tyrosine phosphatase SHP-2 protein (12q24.1).
Mutations of the PTPN11
gene account for 30–60% of all cases of Noonan syndrome.7,8
The mutation associated with Noonan syndrome results in a gain-of-function of SHP-2. This leads to overactivity of the MAPKERK1/2
pathway. SOS1, RAF1 and KRAS did not show any pathogenic sequence.8
It has been suggested that Noonan syndrome, neurofibromatosis type 1 and cardio-facial-cutaneous syndrome should be termed ‘neuro-cardio-facial-cutaneous’ (NCFC) syndromes due to overlapping clinical features and because they all show mutations of the RAS-RAF-ERK-pathway.9
Noonan syndrome is transmitted by autosomal dominant inheritance, and our patient probably suffers from a de novo mutation. Due to the high intrafamilial variability of expression, affected siblings may be almost asymptomatic, but are at risk for progeny with more severe Noonan syndrome associated disease manifestations, such as congenital heart disease and mental retardation. The family members of our patient, especially those wishing to have children, were offered genetic counselling, physical examination and, if necessary, molecular genetic testing.
The frequency of congenital heart disease in Noonan syndrome is estimated to range between 50–90%. A stenotic and often dysplastic pulmonary valve is the most common cardiac anomaly,7
which may have been the reason for the patient’s cardiac surgery in early childhood. The risk of cardiomyopathy and coagulopathy is increased, and complications with general anaesthesia are reportedly more common in patients with Noonan syndrome. Therefore, the patient was seen by a cardiologist and coagulation studies were performed. The patient was advised to inform the anaesthesiologist with respect to his diagnosis in case of future surgery.
Coagulation studies showed slightly decreased factor VII levels and signs of an underlying inflammatory process. Electrocardiogram and echocardiography did not reveal abnormalities.
Data indicate that activating mutations in the PTPN11 gene increase the risk for some tumours including leukaemias.9
However, these malignancies occur early in life and further investigations are normally not required at later age. In our case blood examinations had revealed an increased red blood cell count (RBC). Therefore, we referred our patient to haemato-oncology to reconsider if further analyses were necessary, and to assess whether a myeloproliferative disorder, leukaemia or lymphoma could be excluded.
Blood examinations revealed an increased RBC. We recommended a chest x-ray, a pulmonary function test, and serum analysis of erythropoietin to exclude reactive polyglobulinaemia. The chest x-ray was unremarkable, except for kyphosis. Erythropoietin was low, but still in the normal range (2.8 U/l; normal range 2.6–18.5). The pulmonary function test showed mild respiratory insufficiency.
According to the findings, a haematological malignancy as a cause of polyglobulinaemia appeared less likely. However, FACS analysis revealed abnormal WBC subpopulations. Further, it is still a matter of debate whether Noonan syndrome may be associated with leukaemia and myelodysplastic syndrome. Moreover, the multiple warts were still unexplained. Acquired immunodeficiency due to an underlying haematological reason should be excluded. Therefore, bone marrow biopsy was performed.
Bone marrow biopsy did not show any sign of haematologic malignancy. In addition, qualitative reverse transcriptase polymerase chain reaction (RT-PCR) tests were performed to rule out bcr-abl rearrangement and JAK-2 V617F mutation. These did not show any pathology.
Patients with Noonan syndrome may suffer from several dermatological diseases. Most common are lymphoedemas of the extremities and keratosis pilaris. Only one case has been published of a patient suffering from Noonan syndrome and multiple genital angiokeratomas.10
However, several cases have been reported where patients with Noonan syndrome suffered from cystic lymphatic malformations. Cystic lymphatic malformations are like superficial lymphatic malformations, but present as nodules without epidermal changes. In contrast, lymphangiectasia and superficial lymphatic malformation may mimic genital warts.4,6
While lymphangiectases are dilations of pre-existing vessels, superficial lymphatic malformations are congenital malformations.5
Clinically and (immuno)-histologically it is difficult to distinguish between the two. However, it is possible to differentiate between blood vascular and lymphatic endothelium by immunohistochemistry.
Immunohistochemistry tests with the endothelial marker CD31 and the lymphatic markers podoplanin and Prox-1 were positive (). In conclusion, superficial lymphatic malformations or lymphangiectases seemed more likely. However, superficial lymphatic malformations appear at birth or shortly thereafter. Our patient developed his first skin changes at the age of 9 years. Lymphangiectases may occur if the lymphatic flow is inhibited—for example, by a malignant process. To rule out a malignant process, imaging was performed.
Ultrasound of the abdomen did not show any malformations. However, ultrasound of the inguinal lymph nodes revealed hypodense and centrally hyperdense structures, being compatible with reactive lymph nodes. Computed tomography (CT) and magnetic resonance imaging (MRI) () of the pelvis were performed.
Figure 6 (A) T1 weighted gadolinium enhanced images showing irregularly configured surface of the scrotum with soft tissue proliferation (small arrows). There is increased streaking of tissue surrounding the spermatic cord, which is typical of chronic lymphoedema (more ...)
High signal intensity was seen on the T1 weighted images without contrast enhancement after intravenous gadolinium injection (). T2 weighted () and TIRM images showed water equivalent high signal intensity consistent with scrotal lymphoedema and dilated lymphatic vessels. With imaging it was not possible to differentiate between lympangiectasia and superficial lymphatic malformations. However, there was no sign of malignancy as an underlying cause of lymphatic obstruction.
Lymphangiectasia may also occur in patients with chylous reflux syndrome. Both conditions have been reported in patients with Noonan syndrome. Two different chylous reflux syndromes have been described:11
Type I patients suffer from incompetence of the lymph vessels in the abdomen. Chylus cannot flow into the cisterna chyli, and instead recirculates into the genital and abdominal area. The lymph vessels are seen as megalymphatics in lymphangiography. Lymphangiectases have been described in chylous reflux syndrome type I. In contrast, patients with chylous reflux syndrome type II suffer from absence or hypoplasia of lymphatic vessels. These patients almost never show skin changes and commonly have hypoproteinaemia. While the prognosis in type I patient seems to be good, malignant transformation has been described in those with type II chylous reflux syndrome. The two types can be differentiated by lymphangiography. However, as our patient showed skin changes and did not suffer from hypoproteinaemia, chylous reflux syndrome type I seemed most likely and lymphangiography was dispensed with.