. 2022 Jul 30;17(1):304.

doi: 10.1186/s13023-022-02447-x.

Natural history of Myhre syndrome

David Dawei Yang^{1

2}, Marlene Rio^{3

4}, Caroline Michot^{4

5}, Nathalie Boddaert^{6

7}, Wael Yacoub^{6

7}, Nicolas Garcelon^{1

8}, Briac Thierry^{9

10}, Damien Bonnet^{7

11}, Sophie Rondeau^{4

5}, Dominique Herve¹², Stephanie Guey¹³, Francois Angoulvant^{1

2}, Valerie Cormier-Daire^{14

15}

Affiliations

¹ Centre de Recherche Des Cordeliers, INSERM UMRS 1138 Team 22, Université de Paris, 75006, Paris, France.
² Pediatric Emergency Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015, Paris, France.
³ Université de Paris, Institut IMAGINE, Developmental Brain Disorders Laboratory, INSERM UMR1163, 75015, Paris, France.
⁴ Departement of Medical Genetics, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015, Paris, France.
⁵ Université de Paris, Institut IMAGINE, Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, 75015, Paris, France.
⁶ Paediatric Radiology Department, AP-HP, Hôpital Universitaire Necker Enfants Malades, 75015, Paris, France.
⁷ Université de Paris, Institut IMAGINE, INSERM1163, 75015, Paris, France.
⁸ Université de Paris, Institut IMAGINE, Data Science Platform, INSERM UMR1163, 75015, Paris, France.
⁹ Department of Pediatric Otolaryngology-Head and Neck Surgery, AP-HP, Hôpital Universitaire Necker - Enfants Malades, 75015, Paris, France.
¹⁰ Université de Paris, Human Immunology, Pathophysiology, Immunotherapy/HIPI/INSERM UMR976, Stem Cell Biotechnologies, 75010, Paris, France.
¹¹ M3C-Paediatric Cardiology, AP-HP, Hôpital Universitaire Necker Enfants Malades, 75015, Paris, France.
¹² Department of Neurology, AP-HP Nord, Referral Center for Rare Vascular Diseases of the Brain and Retina (CERVCO), DHU NeuroVasc, INSERM U 1161, 75010, Paris, France.
¹³ Department of Neurology, AP-HP, Hôpital Lariboisière, UMR-S1161, 75010, Paris, France.
¹⁴ Departement of Medical Genetics, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015, Paris, France. valerie.cormier-daire@inserm.fr.
¹⁵ Université de Paris, Institut IMAGINE, Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, 75015, Paris, France. valerie.cormier-daire@inserm.fr.

PMID: 35907855
PMCID: PMC9338657
DOI: 10.1186/s13023-022-02447-x

Natural history of Myhre syndrome

David Dawei Yang et al. Orphanet J Rare Dis. 2022.

. 2022 Jul 30;17(1):304.

doi: 10.1186/s13023-022-02447-x.

Authors

Affiliations

¹ Centre de Recherche Des Cordeliers, INSERM UMRS 1138 Team 22, Université de Paris, 75006, Paris, France.
² Pediatric Emergency Department, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015, Paris, France.
³ Université de Paris, Institut IMAGINE, Developmental Brain Disorders Laboratory, INSERM UMR1163, 75015, Paris, France.
⁴ Departement of Medical Genetics, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015, Paris, France.
⁵ Université de Paris, Institut IMAGINE, Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, 75015, Paris, France.
⁶ Paediatric Radiology Department, AP-HP, Hôpital Universitaire Necker Enfants Malades, 75015, Paris, France.
⁷ Université de Paris, Institut IMAGINE, INSERM1163, 75015, Paris, France.
⁸ Université de Paris, Institut IMAGINE, Data Science Platform, INSERM UMR1163, 75015, Paris, France.
⁹ Department of Pediatric Otolaryngology-Head and Neck Surgery, AP-HP, Hôpital Universitaire Necker - Enfants Malades, 75015, Paris, France.
¹⁰ Université de Paris, Human Immunology, Pathophysiology, Immunotherapy/HIPI/INSERM UMR976, Stem Cell Biotechnologies, 75010, Paris, France.
¹¹ M3C-Paediatric Cardiology, AP-HP, Hôpital Universitaire Necker Enfants Malades, 75015, Paris, France.
¹² Department of Neurology, AP-HP Nord, Referral Center for Rare Vascular Diseases of the Brain and Retina (CERVCO), DHU NeuroVasc, INSERM U 1161, 75010, Paris, France.
¹³ Department of Neurology, AP-HP, Hôpital Lariboisière, UMR-S1161, 75010, Paris, France.
¹⁴ Departement of Medical Genetics, AP-HP, Hôpital Universitaire Necker-Enfants Malades, 75015, Paris, France. valerie.cormier-daire@inserm.fr.
¹⁵ Université de Paris, Institut IMAGINE, Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR1163, 75015, Paris, France. valerie.cormier-daire@inserm.fr.

PMID: 35907855
PMCID: PMC9338657
DOI: 10.1186/s13023-022-02447-x

Abstract

Background: Myhre syndrome (MS) is a rare genetic disease characterized by skeletal disorders, facial features and joint limitation, caused by a gain of function mutation in SMAD4 gene. The natural history of MS remains incompletely understood.

Methods: We recruited in a longitudinal retrospective study patients with molecular confirmed MS from the French reference center for rare skeletal dysplasia. We described natural history by chaining data from medical reports, clinical data warehouse, medical imaging and photographies.

Results: We included 12 patients. The median age was 22 years old (y/o). Intrauterine and postnatal growth retardation were consistently reported. In preschool age, neurodevelopment disorders were reported in 80% of children. Specifics facial and skeletal features, thickened skin and joint limitation occured mainly in school age children. The adolescence was marked by the occurrence of pulmonary arterial hypertension (PAH) and vascular stenosis. We reported for the first time recurrent strokes from the age of 26 y/o, caused by a moyamoya syndrome in one patient. Two patients died at late adolescence and in their 20 s respectively from PAH crises and mesenteric ischemia.

Conclusion: Myhre syndrome is a progressive disease with severe multisystemic impairement and life-threathning complication requiring multidisciplinary monitoring.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Fig. 1**
Computerized tomography angiography. *These images correspond to patient 5*. Transverse reconstruction centered on the celiac trunk: Stenosis of the initial segment of the splenic artery (top arrow) and the post ostial segment of the celiac trunk (left arrow)

**Fig. 2**
Left carotid arteriography. Profile incidence (top), frontal incidence (bottom): Stenosis of the termination of the left internal carotid artery (left arrow) with development of collateral circulation through lenticulo-striated perforating vessels, producing the specific “puff of smoke appearance”of moyamoya syndrome (right arrow). *These images correspond to patient 9*

**Fig. 3**
Magnetic Resonance Angiography, Time of Flight sequence. Coronal reconstruction in Maximum Intensity Projection mode: Stenosis of the end of the left internal carotid artery. *These images correspond to patient 9*

See this image and copyright information in PMC

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References

1. Myhre SA, Ruvalcaba RH, Graham CB. A new growth deficiency syndrome. Clin Genet. 1981;20:1–5. doi: 10.1111/j.1399-0004.1981.tb01798.x. - DOI - PubMed
1. Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destrée A, di Rocco M, Héron D, Jacquemont S, Marlin S, Simon M, Tolmie J, Verloes A, Casanova J-L, Munnich A, Cormier-Daire V. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2011;44:85–88. doi: 10.1038/ng.1016. - DOI - PubMed
1. Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M. Novel SMAD4 mutation causing Myhre syndrome. Am J Med Genet A. 2014;164A:1835–1840. doi: 10.1002/ajmg.a.36544. - DOI - PubMed
1. Michot C, Le Goff C, Mahaut C, Afenjar A, Brooks AS, Campeau PM, Destree A, Di Rocco M, Donnai D, Hennekam R, Heron D, Jacquemont S, Kannu P, Lin AE, Manouvrier-Hanu S, Mansour S, Marlin S, McGowan R, Murphy H, Raas-Rothschild A, Rio M, Simon M, Stolte-Dijkstra I, Stone JR, Sznajer Y, Tolmie J, Touraine R, van den Ende J, Van der Aa N, van Essen T, Verloes A, Munnich A, Cormier-Daire V. Myhre and LAPS syndromes: clinical and molecular review of 32 patients. Eur J Hum Genet EJHG. 2014;22:1272–1277. doi: 10.1038/ejhg.2013.288. - DOI - PMC - PubMed
1. Caputo V, Cianetti L, Niceta M, Carta C, Ciolfi A, Bocchinfuso G, Carrani E, Dentici ML, Biamino E, Belligni E, Garavelli L, Boccone L, Melis D, Andria G, Gelb BD, Stella L, Silengo M, Dallapiccola B, Tartaglia M. A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. Am J Hum Genet. 2012;90:161–169. doi: 10.1016/j.ajhg.2011.12.011. - DOI - PMC - PubMed

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Natural history of Myhre syndrome

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Natural history of Myhre syndrome

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