Co-occurring SHOC2 and PTPN11 mutations in a patient with severe/complex Noonan syndrome-like phenotype

Noonan syndrome (NS) is a heterogeneous disorder caused by activating mutations in the RAS-MAPK signaling pathway. It is associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity, and typical facial features and the inheritance is autosomal dominant. Here, we present a clinical and molecular characterization of a patient with Noonan-like syndrome with loose anagen hair phenotype and additional features including mild psychomotor developmental delay, osteoporosis, gingival hyperplasia, spinal neuroblastoma, intrathoracic extramedullary hematopoiesis, and liver hemangioma. Mutation analysis of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1, MEK2, NRAS, and SHOC2 was conducted, revealing a co-occurrence of two heterozygous previously identified mutations in the index patient. The mutation SHOC2 c.4A > G; p.Ser2Gly represents a de novo mutation, whereas, PTPN11 c.1226G > C; p.Gly409Ala was inherited from the mother and also identified in the brother. The mother and the brother present with some NS manifestations, such as short stature, delayed puberty, keratosis pilaris, café-au-lait spots, refraction error (mother), and undescended testis (brother), but no NS facial features, supporting the notion that the PTPN11 p.Gly409Ala mutation leads to a relatively mild phenotype. We propose that, the atypical phenotype of the young woman with NS reported here is an additive effect, where the PTPN11 mutation acts as a modifier. Interestingly, co-occurrence of RAS-MAPK mutations has been previously identified in a few patients with variable NS or neurofibromatosis-NS phenotypes. Taken together, the results suggest that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway may contribute to the clinical variability observed among NS patients.     

NGS testing for cardiomyopathy: Utility of adding RASopathy‐associated genes

RASopathies include a group of syndromes caused by pathogenic germline variants in RAS‐MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal anomalies. Recently, variants in RASopathy‐associated genes have been reported in individuals with apparently nonsyndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy‐associated genes to cardiomyopathy panels, we tested 11 RASopathy‐associated genes by next‐generation sequencing (NGS), including NGS‐based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Disease‐causing variants were identified in 0.6% (four of 692) of individuals with HCM, including three missense variants in the PTPN11, SOS1, and BRAF genes. Overall, 36 variants of uncertain significance (VUSs) were identified, averaging ～3VUSs/100 cases. This study demonstrates that adding a subset of the RASopathy‐associated genes to cardiomyopathy panels will increase clinical diagnoses without significantly increasing the number of VUSs/case.     

Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants

Overlapping syndromes such as Noonan, Cardio-Facio-Cutaneous, Noonan syndrome (NS) with multiple lentigines and Costello syndromes are genetically heterogeneous conditions sharing a dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway and are known collectively as the RASopathies. PTPN11 was the first disease-causing gene identified in NS and remains the more prevalent. We report seven patients from three families presenting heterozygous missense variants in PTPN11 probably responsible for a disease phenotype distinct from the classical Noonan syndrome. The clinical presentation and common features of these seven cases overlap with the SHORT syndrome. The latter is the consequence of PI3K/AKT signaling deregulation with the predominant disease-causing gene being PIK3R1. Our data suggest that the phenotypic spectrum associated with pathogenic variants of PTPN11 could be wider than previously described, and this could be due to the dual activity of SHP2 (ie, PTPN11 gene product) on the RAS/MAPK and PI3K/AKT signaling.     

Noonan syndrome,the SOS1 gene and embryonal rhabdomyosarcoma

Noonan Syndrome (NS) is an autosomal dominant condition characterized by short stature, facial dysmorphisms, and congenital heart defects, and is caused by mutations in either PTPN11, KRAS, NRAS, SHOC2, RAF1, or SOS1. Furthermore, NS is known for its predisposition to develop cancer, particularly hematological malignancies and specific solid tumors, mainly neuroblastoma and embryonal rhabdomyosacroma (ERMS). Until recently, however, cancer predisposition in NS patients with SOS1 mutations was not reported. Here we present a NS patient with a de novo germline SOS1 mutation (p.Lys728Ile) and ERMS. This heterozygous germline mutation was homozygously present in the ERMS of this patient due to an acquired uniparental disomy (UPD) of chromosome 2. In addition, several other chromosomal aberrations were encountered, some of which are known to recurrently occur in ERMS. Sequence analysis of the SOS1 gene in 20 sporadic ERMS tumors failed to reveal any pathogenic mutations, implicating that SOS1 is not a major player in the development of this tumor outside the context of NS. © 2010 Wiley‐Liss, Inc.     

Prevalence of pathogenic and likely pathogenic variants in the RASopathy genes in patients who have had panel testing for cardiomyopathy

RASopathies are a group of developmental disorders caused by pathogenic variants in the RAS‐MAPK pathway. Cardiomyopathy is a major feature of this group of disorders, specifically hypertrophic cardiomyopathy (HCM). HCM can be the first presenting feature in individuals with RASopathies. We conducted a retrospective study of all individuals who have had a cardiomyopathy gene panel ordered through our institution to determine the prevalence of pathogenic or likely pathogenic variants in RAS pathway genes in individuals with cardiomyopathy. We evaluated variants in the following genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, SHOC2, and SOS1. We reviewed 74 cases with cardiomyopathy, including 32 with HCM, 24 with dilated cardiomyopathy (DCM), nine with both left ventricular noncompaction (LVNC) and DCM, four with LVNC only, two with arrhythmogenic right ventricular cardiomyopathy (ARVC) and three with unspecified cardiomyopathy. We identified four patients (5.41%) with pathogenic or likely pathogenic variants in HRAS, PTPN11 and RAF1 (two individuals). Indication for testing for all four individuals was HCM. The prevalence of pathogenic or likely pathogenic variants in RASopathy genes in our HCM patient cohort is 12.5% (4/32). We conclude that the RASopathy genes should be included on multi‐gene panels for cardiomyopathy to increase diagnostic yield for individuals with HCM.     

Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I

Noonan syndrome (NS) is an autosomal dominant, inherited disorder characterized by facial dysmorphism, congenital heart defects, and reduced postnatal growth. Dysregulated RAS-MAPK signalling is the common molecular basis for NS, a genetically heterogeneous disease. Germline mutations in genes encoding small GTPases of the RAS family (KRAS and NRAS), modulators of RAS function (PTPN11, SOS1 and SHOC2) or downstream signal transducers (RAF1) are causative for NS. SOS1 is the second major gene for NS after PTPN11. Compared to patients with mutations in other genes, SOS1 mutation-positive individuals in general tend to have a more favorable outcome, with less short stature and cognitive impairment. We describe two unrelated patients with NS carrying the same heterozygous SOS1 missense mutation (c.1867T > A/p.F623I). The phenotype of both patients is remarkable as they show uncommon clinical features such as pulmonary lymphangiectasis, congenital pleural effusions, severe feeding problems, and laryngomalacia. These findings may be related to the specific mutation present in our two patients, or be part of the SOS1 phenotype. Detailed clinical assessment of large cohorts of patients with NS and SOS1 mutation is required to clarify this initial observation.     

New Mutations Associated with Rasopathies in a Central European Population and Genotype–Phenotype Correlations

We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty‐five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene.     

Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation-dependent probe amplification (MLPA) testing in all patients and next-generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.     

Providing more evidence on LZTR1 variants in Noonan syndrome patients

Noonan syndrome (NS, OMIM 163950) is a common autosomal dominant RASopathy caused mainly by gain‐of‐function germline pathogenic variants in genes involved in the RAS/MAPK signaling pathway. LZTR1 gene has been associated with both dominant and recessive NS. Here, we present seven patients with NS and variants in the LZTR1 gene from seven unrelated families, 14 individuals in total. The detection rAte of LZTR1 variants in our NS cohort was 4% similar to RAF1 and KRAS genes, indicating that variants in this gene might be frequent among our population. Three different variants were detected, c.742G>A (p.Gly248Arg), c.360C>A (p.His120Gln), and c.2245T>C (p.Tyr749His). The pathogenic variant c.742G>A (p.Gly248Arg) was found in five/seven patients. In our cohort 50% of patients presented heart defects and neurodevelopment delay or learning disabilities, short stature was present in 21% of them and one patient had acute lymphoblastic leukemia. This study broadens the spectrum of variants in the LZTR1 gene and provides increased knowledge of the clinical phenotypes observed in Argentinean NS patients.     

SOS1 mutations in Noonan syndrome: Cardiomyopathies and not only congenital heart defects! Report of six patients including two novel variants and literature review

Noonan syndrome (NS) is caused by mutations in more than 10 genes, mainly PTPN11, SOS1, RAF1, and RIT1. Congenital heart defects and cardiomyopathy (CMP) are associated with significant morbidity and mortality in NS. Although hypertrophic CMP has “classically” been reported in association to RAF1, RIT1, and PTPN11 variants, SOS1 appears to be poorly related to CMP. Patients with NS attending our Center from January 2013 to June 2018 were eligible for inclusion if they carried SOS1 variants and presented with—or developed—CMP. Literature review describing the co‐existence of SOS1 mutation and CMP was also performed. We identified six patients with SOS1 variants and CMP (male to female ratio 2:1) including two novel variants. CMP spectrum encompassed: (a) dilated CMP, (b) nonobstructive hypertrophic CMPs, and (c) obstructive hypertrophic CMPs. Survival is 100%. Literature review included 16 SOS1 mutated in CMP. CMP, mainly hypertrophic, has been often reported in association to RAF1, RIT1, and PTPN11 variants. Differently from previous reports, due to the frequent association of SOS1 variants and CMP in our single center experience, we suggest potential underestimated proportion of SOS1 in pediatric CMPs.     

PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome

After 2006, germline mutations in the KRAS, SOS1, and RAF1 genes were reported to cause Noonan syndrome (NS), in addition to the PTPN11 gene, and now we can find the etiology of disease in approximately 60–70% of NS cases. The aim of this study was to assess the correlation between phenotype and genotype by molecular analysis of the PTPN11, SOS1, KRAS, and RAF1 genes in 59 Korean patients with NS. We found disease-causing mutations in 30 (50.8%) patients, which were located in the PTPN11 (27.1%), SOS1 (16.9%), KRAS (1.7%), and RAF1 (5.1%) genes. Three novel mutations (T59A in PTPN11, K170E in SOS1, S259T in RAF1) were identified. The patients with PTPN11 mutations showed higher prevalences of patent ductus arteriosus and thrombocytopenia. The patients with SOS1 mutations had a lower prevalence of delayed psychomotor development. All patients with RAF1 mutations had hypertrophic cardiomyopathy. Typical facial features and auxological parameters were, on statistical analysis, not significantly different between the groups. The molecular defects of NS are genetically heterogeneous and involve several genes other than PTPN11 related to the RAS-MAPK pathway.     

Clinical and molecular analysis of RASopathies in a group of Turkish patients

?im?ek‐Kiper PÖ, Alanay Y, Gülhan B, Lissewski C, Türky?lmaz D, Alehan D, Çetin M, Utine GE, Zenker M, Boduro?lu K. Clinical and molecular analysis of patients with RASopathies in Turkish patients. The ‘RASopathies’ are a group of disorders sharing many clinical features and a common pathophysiology. In this study, we aimed to clinically evaluate a group of Turkish patients and elucidate the underlying genetic etiology. Thirty‐one patients with a clinical diagnosis of one of the RASopathy syndromes were included in the study. Of these, 26 (83.8%) had a clinical diagnosis of Noonan syndrome, whereas 5 had a clinical diagnosis of either Costello, LEOPARD or cardio‐facio‐cutaneous syndromes. Twenty of 31 (64.5%) patients were found to be mutation positive. Mutations in PTPN11, SOS1 and SHOC2 genes were detected in patients with Noonan syndrome (57.6%). Mutations in MEK1, PTPN11, BRAF and HRAS genes were detected in the remaining. Pulmonary stenosis was the most common (61.5%) cardiac anomaly. Among Noonan syndrome patients with a confirmed mutation, mild intellectual disability tended to be more common in patients with PTPN11 mutation than in those with SOS1 mutation. Hematologic evaluation revealed coagulation defects in three Noonan syndrome patients with a mutation. This is currently the largest clinical and molecular study in Turkish RASopathy patients. Our findings indicate that molecular epidemiology and genotype–phenotype correlations in RASopathies are relatively independent from the ethnic population background.     

Germline BRAF mutations in Noonan,LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum

Noonan, LEOPARD, and cardiofaciocutaneous syndromes (NS, LS, and CFCS) are developmental disorders with overlapping features including distinctive facial dysmorphia, reduced growth, cardiac defects, skeletal and ectodermal anomalies, and variable cognitive deficits. Dysregulated RAS–mitogen‐activated protein kinase (MAPK) signal traffic has been established to represent the molecular pathogenic cause underlying these conditions. To investigate the phenotypic spectrum and molecular diversity of germline mutations affecting BRAF, which encodes a serine/threonine kinase functioning as a RAS effector frequently mutated in CFCS, subjects with a diagnosis of NS (N=270), LS (N=6), and CFCS (N=33), and no mutation in PTPN11, SOS1, KRAS, RAF1, MEK1, or MEK2, were screened for the entire coding sequence of the gene. Besides the expected high prevalence of mutations observed among CFCS patients (52%), a de novo heterozygous missense change was identified in one subject with LS (17%) and five individuals with NS (1.9%). Mutations mapped to multiple protein domains and largely did not overlap with cancer‐associated defects. NS‐causing mutations had not been documented in CFCS, suggesting that the phenotypes arising from germline BRAF defects might be allele specific. Selected mutant BRAF proteins promoted variable gain of function of the kinase, but appeared less activating compared to the recurrent cancer‐associated p.Val600Glu mutant. Our findings provide evidence for a wide phenotypic diversity associated with mutations affecting BRAF, and occurrence of a clinical continuum associated with these molecular lesions. Hum Mutat 0:1–8, 2009. © 2009 Wiley‐Liss, Inc.     

Clinical and molecular characterization of 40 patients with Noonan syndrome

Noonan syndrome (NS, OMIM 163950) is an autosomal dominant disorder, with a prevalence at birth of 1:1000–1:2500 live births, characterized by short stature, facial and skeletal dysmorphisms, cardiovascular defects and haematological anomalies. Missense mutations of PTPN11 gene account for approximately 50% of NS cases, while molecular lesions of other genes of the RAS/MAPK pathway – KRAS, SOS1 and RAF1 – play a minor role in the molecular pathogenesis of the disease. Forty patients were enrolled in the study with a PTPN11 mutation detection rate of 31.5%, including a novel missense mutation, Phe285Ile, in a familial case with high intrafamilial phenotypic variability. All patients negative for PTPN11 mutations were further screened for mutations of the KRAS, SOS1, and RAF1 genes, revealing a Thr266Lys substitution in SOS1 in a single patient, a newborn with a subtle phenotype, characterized by facial dysmorphisms and a mild pulmonic stenosis.     

Genetic and clinical findings in a Chinese cohort of patients with collagen VI‐related myopathies

Collagen VI‐related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with 40 UCMD and 20 BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency of collagen VI or sarcolemma specific collagen VI deficiency. We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were previously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of 1 proband by personal genome machine amplicon deep sequencing for mosaicism. Here we provide clinical, histological and genetic evidence of collagen VI‐related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis provides useful information for genetic counseling of related families.     

Microcephalic osteodysplastic primordial dwarfism type II: Additional nine patients with implications on phenotype and genotype correlation

PCNT encodes a large coiled‐ protein localizing to pericentriolar material and is associated with microcephalic osteodysplastic primordial dwarfism type II syndrome (MOPD II). We report our experience of nine new patients from seven unrelated consanguineous Egyptian families with the distinctive clinical features of MOPD II in whom a customized NGS panel showed homozygous truncating variants of PCNT. The NGS panel results were validated thereafter using Sanger sequencing revealing three previously reported and three novel PCNT pathogenic variants. The core phenotype appeared homogeneous to what had been reported before although patients differed in the severity showing inter and intra familial variability. The orodental pattern showed atrophic alveolar ridge (five patients), rootless tooth (four patients), tooth agenesis (three patients), and malformed tooth (three patients). In addition, mesiodens was a novel finding found in one patient. The novel c.9394‐1G>T variant was found in two sibs who had tooth agenesis. CNS anomalies with possible vascular sequelae were documented in two male patients (22.2%). Simplified gyral pattern with poor development of the frontal horns of lateral ventricles was seen in four patients and mild thinning of the corpus callosum in two patients. Unilateral coronal craniosynstosis was noted in one patient and thick but short corpus callosum was an unusual finding noted in another. The later has not been reported before. Our results refine the clinical, neuroradiological, and orodental features and expand the molecular spectrum of MOPD II.     

Results of next‐generation sequencing gene panel diagnostics including copy‐number variation analysis in 810 patients suspected of heritable thoracic aortic disorders

Simultaneous analysis of multiple genes using next‐generation sequencing (NGS) technology has become widely available. Copy‐number variations (CNVs) in disease‐associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H‐TAD)‐associated genes. Eight hundred ten patients suspected of H‐TAD were analyzed by targeted NGS analysis of 21 H‐TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi‐)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H‐TAD patients.     

Investigation of gene dosage imbalances in patients with Noonan syndrome using multiplex ligation-dependent probe amplification analysis

The RAS-MAPK syndromes are a group of clinically and genetically related disorders caused by dysregulation of the RAS-MAPK pathway. A member of this group of disorders, Noonan syndrome (NS), is associated with several different genes within the RAS-MAPK pathway. To date, mutations in PTPN11, SOS1, KRAS, RAF1 and SHOC2 are known to cause NS and a small group of patients harbour mutations in BRAF, MEK1 or NRAS. The majority of the mutations are predicted to cause an up-regulation of the pathway; hence they are gain-of-function mutations. Despite recent advances in gene identification in NS, the genetic aetiology is still unknown in about ¼ of patients.To investigate the contribution of gene dosage imbalances of RAS-MAPK-related genes to the pathogenesis of NS, a multiplex ligation-dependent probe amplification (MLPA) assay was developed. Two probe sets were designed for seven RAS-MAPK-syndrome-related candidate genes: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2. The probe sets were validated in 15 healthy control individuals and in glioma tumour cell lines. Subsequently, 44 NS patients negative for mutations in known NS-associated genes were screened using the two probe sets. The MLPA results for the patients revealed no gene dosage imbalances. In conclusion, the present results exclude copy number variation of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2 as a common pathogenic mechanism of NS. The validated and optimised RAS-MAPK probe sets presented here enable rapid high throughput screening of further patients with RAS-MAPK syndromes.     

Cleft palate and hypopituitarism in a patient with Noonan‐like syndrome with loose anagen hair‐1

Noonan syndrome (NS), the most common of the RASopathies, is a developmental disorder caused by heterozygous germline mutations in genes encoding proteins in the RAS‐MAPK signaling pathway. Noonan‐like syndrome with loose anagen hair (NSLH, including NSLH1, OMIM #607721 and NSLH2, OMIM #617506) is characterized by typical features of NS with additional findings of macrocephaly, loose anagen hair, growth hormone deficiency in some, and a higher incidence of intellectual disability. All NSLH1 reported cases to date have had an SHOC2 c.4A>G, p.Ser2Gly mutation; NSLH2 cases have been reported with a PPP1CB c.146G>C, p.Pro49Arg mutation, or c.166G>C, p.Ala56Pro mutation. True cleft palate does not appear to have been previously reported in individuals with NS or with NSLH. While some patients with NS have had growth hormone deficiency (GHD), other endocrine abnormalities are only rarely documented. We present a female patient with NSLH1 who was born with a posterior cleft palate, micrognathia, and mild hypotonia. Other findings in her childhood and young adulthood years include hearing loss, strabismus, and hypopituitarism with growth hormone, thyroid stimulating hormone (TSH), and gonadotropin deficiencies. The SHOC2 mutation may be responsible for this patient's additional features of cleft palate and hypopituitarism.