Expanding the phenotypic spectrum of Lenz–Majewski syndrome: facial palsy, cleft palate and hydrocephalus

Wattanasirichaigoon, Duangrurdee; Visudtibhan, Anannit; Jaovisidha, Suphaneewan; Laothamatas, Jiraporn; Chunharas, Amornsri

doi:10.1097/01.mcd.0000127468.11641.b7

Cited by 15 publications

(11 citation statements)

References 14 publications

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“…Based on a human developmental transcriptome, this expression occurs primarily during the first trimester within the forebrain. The head CT reported by Wattanasirichaigoon and colleagues for their patient with relatively mild LMHD, who was later found to have a PTDSS1 mutation, did not show the profound changes documented in our patient. The MRI study reported by Saravia featured hypoplasia mainly of the splenium of the corpus callosum but also of the genu.…”

Section: Discussioncontrasting

confidence: 68%

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Lenz-Majewski Hyperostotic Dwarfism with Hyperphosphoserinuria from a Novel Mutation in PTDSS1 Encoding Phosphatidylserine Synthase 1

Whyte

Blythe

McAlister

et al. 2014

Journal of Bone and Mineral Research

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Lenz-Majewski hyperostotic dwarfism (LMHD) is an ultra-rare Mendelian craniotubular dysostosis that causes skeletal dysmorphism and widely distributed osteosclerosis. Biochemical and histopathological characterization of the bone disease is incomplete and nonexistent, respectively. In 2014, a publication concerning five unrelated patients with LMHD disclosed that all carried one of three heterozygous missense mutations in PTDSS1 encoding phosphatidylserine synthase 1 (PSS1). PSS1 promotes the biosynthesis of phosphatidylserine (PTDS), which is a functional constituent of lipid bilayers. In vitro, these PTDSS1 mutations were gain-of-function and increased PTDS production. Notably, PTDS binds calcium within matrix vesicles to engender hydroxyapatite crystal formation, and may enhance mesenchymal stem cell differentiation leading to osteogenesis. We report an infant girl with LMHD and a novel heterozygous missense mutation (c.829T>C, p.Trp277Arg) within PTDSS1. Bone turnover markers suggested that her osteosclerosis resulted from accelerated formation with an unremarkable rate of resorption. Urinary amino acid quantitation revealed a greater than sixfold elevation of phosphoserine. Our findings affirm that PTDSS1 defects cause LMHD and support enhanced biosynthesis of PTDS in the pathogenesis of LMHD.

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Section: Discussioncontrasting

confidence: 68%

“…In 1983, Gorlin and Whitley noted that “laboratory studies have been unremarkable except for a moderately elevated serum ALP level.” In 2000, Majewski mentioned “low normal” serum ALP . In 2004, Wattanasirichaigoon and colleagues reported normal serum calcium, phosphorus, and ALP levels.…”

Section: Discussionmentioning

confidence: 99%

Lenz-Majewski Hyperostotic Dwarfism with Hyperphosphoserinuria from a Novel Mutation in PTDSS1 Encoding Phosphatidylserine Synthase 1

Whyte

Blythe

McAlister

et al. 2014

Journal of Bone and Mineral Research

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“…We collected DNA and clinical data from five unrelated LMSaffected individuals, including two who were new to this study (subjects 1 and 5) and three who were previously described (subjects 2-4) [8][9][10] ( Fig. 1 and Supplementary Table 1).…”

mentioning

confidence: 99%

“…Cutis laxa is most evident in subject 5. Phenotypic expression is variable: subjects 2 and 4 harbor the same PTDSS1 mutation, and subjects 2-4 were previously described, with progression of phenotypes apparent through comparison with the original report [8][9][10] . Informed consent was obtained for publication of the facial photographs shown.…”

mentioning

confidence: 99%

Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome

Jenkins²,

et al. 2013

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Lenz-Majewski syndrome (LMS) is a syndrome of intellectual disability and multiple congenital anomalies that features generalized craniotubular hyperostosis. By using whole-exome sequencing and selecting variants consistent with the predicted dominant de novo etiology of LMS, we identified causative heterozygous missense mutations in PTDSS1, which encodes phosphatidylserine synthase (PSS ). PSS is one of two enzymes involved in the production of phosphatidylserine. Phosphatidylserine synthesis was increased in intact fibroblasts from affected individuals, and end-product inhibition of PSS by phosphatidylserine was markedly reduced. Therefore, these mutations cause a gain-of-function effect associated with regulatory dysfunction of PSS . We have identified LMS as the first human disease, to our knowledge, caused by disrupted phosphatidylserine metabolism. Our results point to an unexplored link between phosphatidylserine synthesis and bone metabolism.

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“…Only nine affected individuals have been reported to date, and all were sporadic (Braham 1969;Macpherson 1974;Kaye et al 1974;Lenz and Majewski 1974;Robinow et al 1977;Gorlin and Whitley 1983;Chrzanowska et al 1989;Nishimura et al 1997;Saraiva 2000;Wattanasirichaigoon et al 2004). The skeletal changes include progressive hyperostosis of the craniofacial bones with delayed closure of the fontanelles, diaphyseal cortical thickening of the tubular bones, and brachymesophalangy with proximal symphalangism.…”

Section: Introductionmentioning

confidence: 99%

A Japanese patient with a mild Lenz–Majewski syndrome

et al. 2007

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We report on a sclerosing bone dysplasia, associated with cutis laxa, enamel dysplasia, and mental retardation. The patient was a 17-year-old Japanese boy of normal height and muscular build. Cutis laxa with prominent veins in the scalp and abdominal wall and delayed eruption of permanent teeth attracted the attention of clinicians in infancy and adolescence, respectively. The clinical manifestations included a progeroid facial appearance with prognathism, wrinkled skin, and interdigital webbing. The intelligence quotient was estimated at 60. Enamel dysplasia was histologically confirmed. Skeletal changes included calvarial hyperostosis, sclerosis of the skull base, an enlarged, sclerotic mandible, broad clavicles and ribs, and diaphyseal undermodeling of the tubular bones. Metaepiphyseal sclerosis or longitudinal striation was found in the long bones. Metaphyseal equivalents of the axial skeleton showed dense osteosclerosis. These clinical and radiological manifestations overlapped with those of Lenz-Majewski syndrome. Unlike the classical phenotype of the disorder, however, he did not show brachymesophalangy with proximal symphalangism or growth failure. The present case may be considered to fall in the mildest end in the phenotypic continuum of Lenz-Majewski syndrome, suggesting that the clinical spectrum of the disorder may be broader than currently thought.

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Expanding the phenotypic spectrum of Lenz–Majewski syndrome: facial palsy, cleft palate and hydrocephalus

Cited by 15 publications

References 14 publications

Lenz-Majewski Hyperostotic Dwarfism with Hyperphosphoserinuria from a Novel Mutation in PTDSS1 Encoding Phosphatidylserine Synthase 1

Lenz-Majewski Hyperostotic Dwarfism with Hyperphosphoserinuria from a Novel Mutation in PTDSS1 Encoding Phosphatidylserine Synthase 1

Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome

A Japanese patient with a mild Lenz–Majewski syndrome

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