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A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation—a review of the literature

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Abstract

Noonan syndrome (NS) is a genetic condition presenting with typical facies, cardiac defects, short stature, variable developmental deficit, cryptorchidism, skeletal, and other abnormalities. Germline mutations in genes involved in the RAS/MAPK signaling have been discovered to underlie NS. Recently, missense mutations in RIT1 have been reported as causative for individuals with clinical signs of NS. We report on a 2.5-year-old boy with NS phenotype with a novel heterozygous change in the RIT1 gene. The patient was born prematurely from pregnancy monitored for polyhydramnios. At 7 months of age, non-immune neutropenia and splenomegaly have been observed. During the severe pneumonia at 10 months, significant progression of hepatosplenomegaly, leukopenia with monocytosis (15–29 %), and thrombocytopenia occurred. Bone marrow evaluation showed myeloid hyperplasia and monocytosis, suggestive of myeloproliferative syndrome. Clinical phenotype (facial dysmorphism, soft hair, short neck, broad chest, widely spaced nipples, mild pectus carinatum, deep palmar creases, unilateral cryptorchidism), and moderate pulmonary valve stenosis with mild psychomotor delay were indicative of NS. DNA analysis identified a de novo heterozygous variant c.69A >T, p.(Lys23Asn) in exon 2 of the RIT1 gene, presumed to be causative.

Conclusion: We present a patient with a clinical suspicion of NS carrying a novel substitution in RIT1 and hematologic findings not being observed in RIT1 positive patients to date. Thus, the case broadens variability of hematologic symptoms in RIT1 positive NS individuals.

What is known:

• Noonan syndrome is a common genetically heterogeneous disorder of autosomal dominant inheritance characterized by craniofacial dysmorphism, short stature, congenital heart defects, variable cognitive deficit, and other anomalies.

What is new:

• We report on a 2.5-year-old male patient with clinical signs of NS and hematologic abnormalities, in whom a novel heterozygous substitution in RIT1 with probable pathogenicity was detected.

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Abbreviations

BRAF:

V-raf murine sarcoma viral oncogene homolog B

CBL:

Cbl proto-oncogene

CMV:

Cytomegalovirus

COSMIC:

Catalog of somatic mutations in cancer

dbSNP:

Database of single nucleotide polymorphisms

DNA:

Deoxyribonucleic acid

ELK1:

Member of ETS oncogene family

EBV:

Epstein-Barr virus

GTP:

Guanosine-5′-triphosphate

HCM:

Hypertrophic cardiomyopathy

HGMD:

Human Gene Mutation Database

HHV-6:

Human herpesvirus 6

KRAS:

Kirsten rat sarcoma viral oncogene homolog

LZTR1:

Leucine-zipper-like transcription regulator 1

MAP2K1:

Mitogen-activated protein kinase kinase 1

MAP2K2:

Mitogen-activated protein kinase kinase 2

NHLBI:

National Heart, Lung, and Blood Institute

NRAS:

Neuroblastoma RAS viral (v-ras) oncogene homolog

NS:

Noonan syndrome

OFC:

Occipitofrontal circumference

PCR:

Polymerase chain reaction

PTPN11:

Tyrosine-protein phosphatase non-receptor type 11

RAF1:

V-raf-1 murine leukemia viral oncogene homolog 1

RAS:

Rat sarcoma protein family

RAS/MAPK:

RAS-mitogen-activated protein kinases

RRAS:

Related RAS viral (R-RAS) oncogene homolog

RSV:

Respiratory syncytial virus

RIT1:

Ras-like without CAAX 1

SHOC2:

Soc-2 suppressor of clear homolog

SIFT:

Sorting Intolerant From Tolerant

SOS1:

Son of sevenless homolog 1

SOS2:

Son of sevenless homolog 2

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Acknowledgments

We would like to thank the family members for participating in the study. This work was supported by grant for conceptual development of research organization University Hospital Motol 00064203 from the Ministry of Health of the Czech Republic.

Author’s contributions

MN wrote the article, critically reviewed the article, and contributed to data collection. SV, FF, and MS contributed to data collection and reviewed the article. AK was helpful in writing the article and critically reviewed the article.

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Authors and Affiliations

  1. Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic

    Michaela Nemcikova, Sarka Vejvalkova & Anna Krepelova

  2. Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic

    Filip Fencl

  3. Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, V Úvalu 84, 150 06, Prague, Czech Republic

    Martina Sukova

Authors
  1. Michaela Nemcikova
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  2. Sarka Vejvalkova
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  3. Filip Fencl
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  4. Martina Sukova
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  5. Anna Krepelova
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Corresponding author

Correspondence to Michaela Nemcikova.

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Funding

This study was funded by grant for conceptual development of research organization University Hospital Motol 00064203 from the Ministry of Health of the Czech Republic.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Communicated by Beat Steinmann

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Nemcikova, M., Vejvalkova, S., Fencl, F. et al. A novel heterozygous RIT1 mutation in a patient with Noonan syndrome, leukopenia, and transient myeloproliferation—a review of the literature. Eur J Pediatr 175, 587–592 (2016). https://doi.org/10.1007/s00431-015-2658-6

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  • DOI: https://doi.org/10.1007/s00431-015-2658-6

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