LEOPARD syndrome: Clinical diagnosis in the first year of life
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.
Figures in this publication
Available from: Dino Gibertoni
- "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
Available from: dmm.biologists.org
- "Pectus excavatum and pectus carinatum are also common features of NS and LS. These sternal abnormalities have been observed in up to 95% of individuals with NS and 50% of those with LS (Sharland et al., 1992; Digilio et al., 2006). Pectus excavatum and carinatum have also been observed in Ptpn11 Y279C LS mice Fig. 5 "
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ABSTRACT: Induced global disruption of the Ptpn11 gene in mice that encodes the SHP-2 tyrosine phosphatase results in severe skeletal abnormalities. To understand the extent to which skeletal abnormalities can be attributed to perturbation of SHP-2 function in bone-forming osteoblasts and chondrocytes, we generated mice in which disruption of Ptpn11 is restricted to mesenchymal stem cells (MSC) and their progeny that include both cell types. MSC lineage specific SHP-2 knockout (MSC SHP-2 KO) mice exhibited postnatal growth retardation, limb and chest deformity and calvarial defects. These skeletal abnormalities were associated with an absence of mature osteoblasts and massive chondrodysplasia with a vast increase in the number of terminally differentiated hypertrophic chondrocytes in affected bones. Activation of mitogen activated protein kinases and protein kinase B/AKT was impaired in bone forming cells of MSC SHP-2 KO mice, which provides an explanation for the skeletal defects that developed. These findings reveal a cell autonomous role for SHP-2 in bone forming cells in mice in the regulation of skeletal development. The results are relevant to an understanding of the pathophysiology of skeletal abnormalities observed in humans with germline mutations in the PTPN11 gene.
Disease Models and Mechanisms 09/2013; 6(6). DOI:10.1242/dmm.012849 · 4.97 Impact Factor
Available from: Bruno Marino
- "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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