Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma

APRIL - JUNE 2000s VOL. 46(2) CONTENTS EDITORIAL Duplicate and salami publications Philip Abraham ORIGINAL ARTICLE The Evaluation of Cerebral Oxygenation by Oximetry in Patients with Ischaemic Stroke Demet G, Talip A, Nevzat U, Serhat Ö, Gazi Ö The Palm Print as a Sensitive Predictor of Difficult Laryngoscopy in Diabetics: A Comparison with Other Airway Evaluation Indices Vani V, Kamath SK, Naik LD Giant Prosthesis for Reinforcement of Visceral Sac for Complex Bilateral and Recurrent Inguinal Hernias: A Prospective Evaluation Thapar V, Rao P, Prabhu R, Desai C, Singh AS, Supe AN Effect of Early Mobilisation on Grip Strength, Pinch Strength and Work of Hand Muscles in Cases of Closed Diaphyseal Fracture Radius-Ulna Treated With Dynamic Compression Plating Solanki PV, Mulgaonkar KP, Rao SA A Study of an Epidemic of Acute Respiratory Disease in Jaipur Town Mathur ML, Yadav SP, Tyagi BK CASE REPORT Scleredema Adultorum Parmar RC, Bavdekar SB, Bansal S, Doraiswamy A, Khambadkone S An Intragastric Trichobezoar: Computerised Tomographic Appearance Morris B, Shah ZK, Shah P Sprengels Deformity: Anaesthesia Management Dave S, Naik LD Neurofibromatosis-Noonan Syndrome or LEOPARD Syndrome? A Clinical Dilemma Tullu MS, Muranjan MN, Kantharia VC, Parmar RC, Sahu DR, Bavdekar SB, (Late) Bharucha BA Eisenmenger Syndrome in Pregnancy Kansaria JJ, Salvi VS Imaging Findings in a Giant Hepatic Artery Aneurysm Parmar H, Shah J, Shah B, Patkar D, Varma R Malrotation of the gut manifested during pregnancy Hardikar JV Isolated Tuberculous Hepatic Abscess in a Non-Immunocompromised Patient Balsarkar D, Joshi MA Giant Cell Tumour of Talar Body Bapat MR, Narlawar RS, Pimple MK, Bhosale PB

EDUCATION FORUM The Art and Science of Presentation: The Poster Supe AN, Sahu DR E-MEDICINE Information Retrieval in Medicine: Overview and Applications Nadkarni PM The Art and Science of Web-Based Literature Search: The MEDLINE Sahu DR, Ramakantan R, Bavdekar SB IMAGES IN MEDICINE Images in Medicine: Apert Syndrome Hosalkar HS, Shah H, Gujar P, Chaudhari A IMAGES IN RADIOLOGY Images in Radiology: Type III Growing Skull Fracture Parmar RC, Bavdekar SB IMAGES IN PATHOLOGY Images in Pathology: Verrucous Haemangioma Rupani AB, Madiwale CV, Vaideeswar P SPECIAL ARTICLE Non-pathology: The Bedrock of Pathology Kothari MVL, Mehta LA, Kothari VM REVIEW ARTICLE Antinuclear Antibodies: Clinical Applications Wanchu A Non-invasive Respiratory Monitoring in Paediatric Intensive Care Unit Nadkarni UB, Shah AM, Deshmukh CT DRUG REVIEW Eptifibatide: In the treatment of acute coronary syndromes Oak MA, Rege NN Capcil: Drug therapy monitoring software Ray SB, Rege NN

Neurofibromatosis-Noonan Syndrome or LEOPARD Syndrome? A Clinical Dilemma Tullu MS, Muranjan MN, Kantharia VC, Parmar RC, Sahu DR, Bavdekar SB, (Late) Bharucha BA Genetics Division, Department of Paediatrics, Seth G. S. Medical College & K. E. M. Hospital, Parel, Mumbai - 400 012, India.

Abstract: Neurofibromatosis (NF), Noonan syndrome (NS), and LEOPARD syndrome are all autosomal dominant conditions, each being a distinct clinical entity by itself. Rarely, one encounters cases with features of NF and NS and is termed as the ‘Neurofibromatosis-Noonan syndrome’ (NF-NS). The authors report a clinical dilemma with major clinical features of the NF-NS syndrome and LEOPARD syndrome co-existing in the same patient. Also, features of Noonan syndrome and LEOPARD syndrome are compared with the case reported. (J Postgrad Med 2000; 46:98-100)

Key Words: Neurofibromatosis, Noonan syndrome, LEOPARD syndrome, Lentigines, Pulmonary stenosis, Cafe-au-lait spots Noonan syndrome (NS) is fairly common and occurs with an incidence of 1:1000 to 1:2500 live births1. Neurofibromatosis (NF) is also common and affects 1 in 3500 individuals2. A few patients with characteristics of both NF and NS have been described and are called as the Neurofibromatosis-Noonan syndrome (NF-NS)1. LEOPARD syndrome is a rare multisystemic disorder characterised by Lentigines, ECG abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormalities of genitalia, Retardation of growth, and Deafness3. There are many features common to NF-NS and LEOPARD syndrome as seen in this interesting case. Case Report A 15 months-old-male child born of a third degree consanguineous marriage presented with global developmental delay and recurrent respiratory infections. His antenatal and birth history were normal. At the age of two months, he had refusal to feed and breathlessness and was diagnosed to have pulmonary stenosis for which a balloon valvoplasty was successfully performed. An episode of fever provoked a generalised tonic clonic convulsion at the age of eight months and was followed by right hemiparesis. A CT scan of the brain done at that time revealed left cerebral hemispheric angiomatous pial vascular malformation and mild cerebral cortical atrophy (Figure 1). The CSF examination was normal and EEG showed left hemispheric slowing with low amplitude. On examination, he had growth failure, microcephaly, and decreased ear length. Craniofacial dysmorphisms included coarse facies, depressed nasal bridge, bilateral ptosis, and low set ears. The child had right hemiparesis, pectus carinatum, right-sided cryptorchidism with poorly developed scrotum, and multiple pigmented macules along with multiple cafe-au-lait spots. A grade IV/VI systolic murmur was present in the pulmonary area with a single second heart sound. The developmental age was six months. At the age of four years additional features noticed in-

cluded prominent upper lip, anti-mongoloid slant of palpebral fissures, high arched palate, retrognathia, epicanthic folds, midface hypoplasia, and left hand simian crease (Figure 2). The developmental age was one year with a developmental quotient of 39. Multiple pigmented spots of size 1 to 5 mm were noticed all over the body and cafe-au-lait spots ranging from 1 to 4 cm were also present. There was a firm swelling in the right axilla about 3 x 3 cm in size (Figure 2). Investigations including complete blood count, renal function tests, arterial blood gases, and bleeding profile were normal, as was the fundus. ECG showed right ventricular hypertrophy. Abdominal ultrasonography was normal. Colour Doppler showed severe stenosis of the pulmonary artery with a transvalvular gradient of 98 mmHg. His brainstem evoked response audiometry revealed bilateral moderate sensorineural hearing loss. The karyotype was normal. Skin biopsy of the smaller pigmented macules was suggestive of lentigines with an increase in the rete ridges in the basal layer. The parents were normal and did not have neurocutaneous lesions on Wood’s lamp examination. Discussion Cases with overlapping clinical features of NS and NF have been reported (Neurofibromatosis-Noonan syndrome)1,4-7. The LEOPARD syndrome is comparatively rare and there are no reports of coexisting NS, though 2% of the cases with NS have lentigines1. The comparative features of NS, LEOPARD syndrome, and our case are presented in Table 1. As can be noted from the table, most of the diagnostic criteria for the LEOPARD syndrome except the ECG abnormalities (or cardiomyopathy) were present in our case. Though the craniofacial features in our case were characteristic of NS, webbing of neck was absent. The presence of significant cafe-au-lait spots prompted a careful search for other features of NF-1, which were absent. The child did have an axillary swelling, which could very well be a neurofibroma. Unfortu-

Table 1: Comparison of major diagnostic features of Noonan syndrome, LEOPARD syndrome and the present case1,3,8,9 Feature Growth Performance Epicanthic folds Ptosis of eyelids Hypertelorism Low nasal bridge Down slanting palpebral fissures Ears Upper lip

Mandible Palate Short/webbed neck Excess nuchal skin with low posterior hairline Thorax

Skeletal anomalies Cardiac anomalies

Skin

Genitalia

Deafness Miscellaneous

Noonan syndrome Short stature (50%) Mild mental retardation (33%) Present Present Present Present Present

LEOPARD syndrome Growth retardation (35%) Mild mental retardation (30%) Absent Present Present (25%) Absent Absent

Present case Short stature Mental retardation Present Present Present Present Present

Low set posteriorly rotated with thick helix &/or abnormal auricles (90%) Deeply grooved philtrum with high wide peaks of vermilion border of upper lip (95%) Moderate retrognathia High arched (45%) Present Present (55%)

Prominent ears

Low set ears

Normal

Prominent upper lip

Mandibular prognathism Absent Absent

Retrognathia High arched Absent Absent

Shield chest Pectus excavatum or carinatum or both (70%) Cubitus valgus (50%) Vertebral anomalies Pulmonary valvular stenosis (50%) Asymmetrical septal hypertrophy (10%) Atrial septal defects (10%) Patent ductus arteriosus Branch pulmonary artery stenosis Left axis deviation (33%) Cafe-au-lait spots (10%) Lentigines (2%) Pigmented nevi (25%) Cryptorchidism (60%) Small penis

Pectus carinatum or excavatum

Pectus carinatum

Kyphoscoliosis Winging of scapulae Mild pulmonary valvular or infundibular stenosis (50%) Obstructive cardiomyopathy (20%) Aortic or mitral stenosis ECG changes: prolonged P-R and QRS; abnormal P waves Cafe-au-lait spots Lentigines

Absent

Cryptorchidism (15%) Hypospadias Hypogonadism Sensorineural (20%) Renal agenesis / hypoplasia Hyposmia

Right cryptorchidism

Sensorineural Cerebral arteriovenous malformation Simian crease Congenital lymphatic abnormalities (20%)

nately, it could not be biopsied due to the high-risk cardiac status of the patient. Neurofibromas rarely develop before six years of age as do the other major manifestations of NF such as the Lisch nodules2. Our patient will need a close follow-up over the years to detect an evolving NF-1 phenotype. As a point of interest, both NF and LEOPARD syndrome have an autosomal dominant inheritance2,3. An apparent autosomal dominant transmission has been reported in NS as well8. All the three syndromes have a variable expression so that it is not mandatory for all the clinical features to be present to make a diagnosis2,3,8. Various theories have been proposed to explain the coexistence of NF and NS. These include- a coincidental event, new mutation, predisposition of NS to neural crest

Pulmonary stenosis

Cafe-au-lait spots Lentigines

Sensorineural Left cerebral angiomatous pial vascular malformation Left simian crease

dysplasias, etc4-7. None of these have been substantiated beyond doubt. The gene for NF-1 is located at 17q11.210 and that for NS at 12q22-ter8. As yet there is no evidence to suggest the existence of a distinct locus for NF-NS. It is hoped that with the rapid advances in the field of molecular genetics, it will be possible to solve clinical dilemmas like the present case. Acknowledgements We thank our Dean for his permission for the publication and Dr. Deepak Parikh, Consultant Dermatologist, Bombay Hospital for performing and interpreting the skin biopsy.

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