LEOPARD syndrome: Clinical diagnosis in the first year of life

Medical Genetics and Pediatric Cardiology, Bambino Gesù Hospital, Rome, Italy.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 04/2006; 140(7):740-6. DOI: 10.1002/ajmg.a.31156
Source: PubMed


LEOPARD syndrome (LS) is an autosomal dominant syndrome characterized by multiple lentigines and café-au-lait spots, electrocardiographic-conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormalities of the genitalia in males, retardation of growth, and deafness. LS shares many features with Noonan syndrome (NS), in which lentigines and deafness are usually not present. Molecular studies have shown that LS and NS are allelic disorders, caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q22-qter. The clinical diagnosis of LS is generally difficult in the first months of life because the distinctive lentigines are generally not present at birth and develop during childhood. From January 2002 to December 2004, we suspected LS clinically in 10 patients admitted to our genetic counseling services in the first 12 months of life. A PTPN11 gene mutation was detected in 8/10 (80%) patients. In one patient without a PTPN11 mutation a subsequent clinical diagnosis of neurofibromatosis type 1 (NF1) was made, following the evaluation of the mother, who had previously undiagnosed classic NF1. The age of LS patients with PTPN11 mutation ranged between 1 and 11 months (mean age +/- SD 7.5 +/- 3.96 months). Review of the clinical characteristics of patients with LS confirmed by molecular study during the first year of life demonstrates that the diagnosis of LS in the first months of age can be clinically suspected in patients presenting with three main features, that is, characteristic facial features (100%), hypertrophic cardiomyopathy (HCM) (87%), and cafe-au-lait spots (75%). Characteristic facial features can be mild or severe, and consist of hypertelorism, downslanting palpebral fissures, ptosis, and dysmorphic ears. The clinical suspicion of LS may be confirmed by molecular screening for PTPN11 mutations. An early diagnosis of the disease is useful for the prospective care of associated medical problems and for precise genetic counseling.

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    • "Mean adult H of 138 cm was reported [Van Eeghen et al., 1999]. In Noonan syndrome with multiple lentigenes (NSML; previously referred to as LEOPARD syndrome), birth W is normal or above average in 1/3 [Digilio et al., 2006]. Retardation of growth is reported in about 25% below the 3rd centile in H, and final height (FH) is 85% below the 3rd centile [Gorlin et al., 1971; Voron et al., 1976; Sarkozy et al., 2008]. "
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    ABSTRACT: RASopathies are developmental disorders caused by heterozygous germline mutations in genes encoding proteins in the RAS-MAPK signaling pathway. Reduced growth is a common feature. Several studies generated data on growth, final height (FH), and height velocity (HV) after growth hormone (GH) treatment in patients with these disorders, particularly in Noonan syndrome, the most common RASopathy. These studies, however, refer to heterogeneous cohorts in terms of molecular information, GH status, age at start and length of therapy, and GH dosage. This work reports growth data in 88 patients affected by RASopathies with molecularly confirmed diagnosis, together with statistics on body proportions, pubertal pattern, and FH in 33, including 16 treated with GH therapy for proven GH deficiency. Thirty-three patients showed GH deficiency after pharmacological tests, and were GH-treated for an average period of 6.8 ± 4.8 years. Before starting therapy, HV was -2.6 ± 1.3 SDS, and mean basal IGF1 levels were -2.0 ± 1.1 SDS. Long-term GH therapy, starting early during childhood, resulted in a positive height response compared with untreated patients (1.3 SDS in terms of height-gain), normalizing FH for Ranke standards but not for general population and Target Height. Pubertal timing negatively affected pubertal growth spurt and FH, with IGF1 standardized score increased from -2.43 to -0.27 SDS. During GH treatment, no significant change in bone age velocity, body proportions, or cardiovascular function was observed. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2015; DOI:10.1002/ajmg.a.37260 · 2.16 Impact Factor
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    • "Generalized neonatal ichthyosis was found in single patients with SHOC2 and MEK2 mutations. Of note, all these skin features were present in the first months of life, with the only exception of lentigines, which developed in 9 of the 11 cases with molecularly confirmed LS after the second year of life ( table 4 ) [Digilio et al., 2006a]. "
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    ABSTRACT: Diagnosis within Noonan syndrome and related disorders (RASopathies) still presents a challenge during the first months of life, since most clinical features used to differentiate these conditions become manifest later in childhood. Here, we retrospectively reviewed the clinical records referred to the first year of life of 57 subjects with molecularly confirmed diagnosis of RASopathy, to define the early clinical features characterizing these disorders and improve our knowledge on natural history. Mildly or markedly expressed facial features were invariably present. Congenital heart defects were the clinical issue leading to medical attention in patients with Noonan syndrome and LEOPARD syndrome. Feeding difficulties and developmental motor delay represented the most recurrent features occurring in subjects with cardiofaciocutaneous syndrome and Costello syndrome. Thin hair was prevalent among SHOC2 and BRAF mutation-positive infants. Café-au-lait spots were found in patients with LS and PTPN11 mutations, while keratosis pilaris was more common in individuals with SOS1, SHOC2 and BRAF mutations. In conclusion, some characteristics can be used as hints for suspecting a RASopathy during the first months of life, and individual RASopathies may be suspected by analysis of specific clinical signs. In the first year of life, these include congenital heart defects, severity of feeding difficulties and delay of developmental milestones, hair and skin anomalies, which may help to distinguish different entities, for their subsequent molecular confirmation and appropriate clinical management.
    Molecular syndromology 09/2011; 1(6):282-289. DOI:10.1159/000331266
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    • "In these patients, the clinical differentiation from NS might be difficult during infancy and early childhood. The occurrence of distinctive association of signs, including HCM, sensorineural deafness, and caféau-lait spots represents an important diagnostic handle in these young patients [Digilio et al., 2006]. Sarkozy et al. [2009a] provide an updated review of the clinical and molecular genetics aspects of this disorder. "
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    ABSTRACT: Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.
    Molecular syndromology 02/2010; 1(1):2-26. DOI:10.1159/000276766
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