LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria

Abstract

Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are well-defined entities. The association of both disorders is called neurofibromatosis-Noonan syndrome (NFNS), a disorder that has been related to mutations in the NF1 gene. Both NS and NFNS display phenotypic overlapping with LEOPARD syndrome (LS), and differential diagnosis between these two entities often represents a challenge for clinicians. We report on three patients (two brothers and a not-related patient) diagnosed as having NFNS. They fulfilled NF1 diagnostic criteria and had some features of NS. The three of them had hypertophic cardiomyopathy while neurofibromas, Lisch nodules, and unidentified bright objects on MRI were absent. PTPN11 gene assays revealed a T468M mutation, typical of LS. Thorough clinical examinations of the patients revealed multiple lentigines, which were considered to be freckling in the initial evaluation. We conclude that NF1 clinical criteria should be used with caution in patients with features of NS. Patients with hyperpigmented cutaneous spots associated with cardiac anomalies, even if fulfilling the minimal NF1 criteria for diagnosis, should be strongly considered for LS diagnosis.

LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies

“…For example, Wu et al [19] reported a de novo NF1 mutation in a woman with a prior diagnosis of LS. Moreover, Carcavilla et al [20] reported three children who filled NF1 clinical criteria but were diagnosed with LS and carried the PTPN11 mutation p.( Thr468Met ), the same mutation detected in our patients. Carcavilla et al [20] suggested that a distinguishing feature for LS might be the diffuse pattern of lentigines, even if they seem to appear later in life than CALMs; this is in accord with our personal observations.…”

“…Moreover, Carcavilla et al [20] reported three children who filled NF1 clinical criteria but were diagnosed with LS and carried the PTPN11 mutation p.( Thr468Met ), the same mutation detected in our patients. Carcavilla et al [20] suggested that a distinguishing feature for LS might be the diffuse pattern of lentigines, even if they seem to appear later in life than CALMs; this is in accord with our personal observations. The patients described in this previous report had cardiomyopathy but lacked other features typical of LS, such as deafness or genital abnormalities.…”

LEOPARD Syndrome: A Variant of Noonan Syndrome Strongly Associated With Hypertrophic Cardiomyopathy

“…Noonan syndrome-neurofibromatosis syndrome, which is related to mutations in the NF1 gene 34 congenital heart condition such as hypertrophic cardiomyopathy in patients with Noonan syndrome-neurofibromatosis makes it advisable to start with a genetic study of PTPN11 rather than with NF1. 35 Multiple lentigines and cafe´au lait spots are common in all 3 entities. Just as cafe´au lait spots increase in number and size with age in these entities, multiple lentigines are rare in younger children.…”

LEOPARD Syndrome Without Hearing Loss or Pulmonary Stenosis: A Report of 2 Cases

“…Manifestations may be present from birth, but they usually appear when the child is around 4 or 5 years of age and may even first present in puberty. 2,4,5 Café au lait macules, which are somewhat larger than lentigines, can be seen in 70% to 80% of patients. Lesions that are darker have been called black coffee macules.…”