Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non‐lethal form of Raine syndrome

Tamai, Kazuya; Tada, Kazuhiro; Takeuchi, Akihito; Nakamura, Makoto; Marunaka, Hidenori; Washio, Yosuke; Tanaka, Hiroyuki; Miya, Fuyuki; Okamoto, Nobuhiko; Kageyama, Misao

doi:10.1002/ajmg.a.38598

Cited by 15 publications

(19 citation statements)

References 17 publications

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“…Overall, we present follow-up data of non-lethal RS in the single largest cohort of patients and with the longest follow up duration, the oldest of our patients being 18 years old at present. We, therefore, can support the previous data that life expectancy for these patients goes beyond childhood [19][20][21][22]. We found great heterogeneity in terms of the rate of complications emerging during follow-up.…”

Section: Discussionsupporting

confidence: 88%

Natural history of non-lethal Raine syndrome during childhood

Mameli

Zichichi

Mahmood

et al. 2020

Orphanet J Rare Dis

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Background: Raine syndrome (RS) is a rare autosomal recessive disorder caused by biallelic loss-of-function mutations of FAM20C. The most common clinical features are microcephaly, exophthalmos, hypoplastic nose and severe midface hypoplasia, leading to choanal atresia. The radiological findings include generalized osteosclerosis and brain calcifications. RS is usually lethal during the neonatal period due to severe respiratory distress. However, there exists a non-lethal RS form, the phenotype of which is extremely heterogeneous. There is paucity of data about clinical course and life expectancy of these patients. Results: This is the first description of follow-up features of non-lethal RS patients. Moreover, we present three unpublished cases. There are five Asian and two Arab patients. All were born to consanguineous parents. The most common neonatal comorbidity was respiratory distress secondary to choanal atresia. A variable degree of neurodevelopmental delay was seen in the majority of our cases and seizures and hearing or vision involvement were also frequent. Neurological and orthopedic issues were the most frequent complications seen at follow-up in our group. Persistent hypophosphatemic rickets was the most striking endocrinological manifestation, which was scarcely responsive to therapy with phosphate salts and alfacalcidol. Life expectancy of our patients goes beyond childhood, with the oldest of those described being 18 years old at present. Conclusions: Manifestations of RS in those surviving the neonatal period are being increasingly recognized. Our study supports previous findings and provides clinical and biochemical observations and data from longer follow up. Finally, we propose multidisciplinary follow up for patients with non-lethal RS.

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Section: Discussionsupporting

confidence: 88%

Natural history of non-lethal Raine syndrome during childhood

Mameli

Zichichi

Mahmood

et al. 2020

Orphanet J Rare Dis

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“…Ectopic soft tissue calcifications and calcification in different organ systems such as ovaries, liver, and spleen have been also reported in RS [20,21,25]. It seems that intracranial calcification is a consistent feature of the disease and independent from serum calcium and phosphate, as it has been described at birth and/ or antenatal USG [2,31,38]. Furthermore, nephrocalcinosis also appears to develop independently from calcium and phosphate status since it was present at the first day of life in our case and has also been described in a case with normal serum calcium and phosphate levels [20].…”

Section: Discussionmentioning

confidence: 83%

“…Although this mechanism is clearly known today, biochemical data of previous RS cases have not always been reported (Suppl. Table 2) [2,30,31,[36][37][38]. FGF23 levels could be studied in a few cases and shown to be elevated [4,5,28,39], but elevated urinary phosphate excretion had been shown in almost all cases including the case herein [24,27,28,34,39].…”

Section: Discussionmentioning

confidence: 99%

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age

et al. 2020

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Raine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-abone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…To date, 28 pathogenic variants in FAM20C have been reported in association with Raine syndrome of which 19/28 are missense variants (Acevedo et al, ; Boissel et al, ; Elalaoui et al, ; Fradin et al, ; Kochar et al, ; Mahmood N., 2014; Rafaelsen et al, ; Seidahmed et al, ; Sheth et al, ; Simpson et al, ; Simpson et al, ; Takeyari et al, ; Tamai et al, ; Whyte et al, ) (Table S1). These 19 reported pathogenic missense variants and polymorphisms identified in nominally healthy reference population were mapped onto the 3D structure of the FAM20C protein (Berman et al, ; Lek et al, ) (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…To date, 28 different mutations in FAM20C have been reported in association with Raine syndrome, including missense variants ( n = 19), nonsense variants ( n = 1), splice site variants ( n = 5), and complex rearrangements ( n = 3) (Ababneh et al, ; Acevedo et al, ; Boissel et al, ; Elalaoui et al, ; Fradin et al, ; Kochar et al, ; Mahmood, Donne, Weber, & Dharmaraj, ; Rafaelsen et al, ; Seidahmed et al, ; Sheth et al, ; Simpson et al, ; Simpson et al, ; Takeyari et al, ; Tamai et al, ; Whyte et al, ). The genotype–phenotype correlation is unknown.…”

Section: Introductionmentioning

confidence: 99%

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

Hung

Rodrı́guez

Roberts

et al. 2019

American J of Med Genetics Pt A

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Raine syndrome is a rare, autosomal recessive, osteosclerotic bone dysplasia due to pathogenic variants in FAM20C. The clinical phenotype is characterized by generalized osteosclerosis affecting all bones, cerebral calcifications, and craniofacial dysmorphism.Most cases present during the neonatal period with early lethality due to pulmonary hypoplasia and respiratory compromise while only few affected individuals have been reported to survive into adulthood. FAM20C is a ubiquitously expressed protein kinase that contains five functional domains including a catalytic domain, a binding pocket for FAM20A and three distinct N-glycosylation sites. We report a newborn infant with a history of prenatal onset fractures, generalized osteosclerosis, and craniofacial dysmorphism and early lethality. The clinical presentation was highly suggestive of Raine syndrome. A homozygous, novel missense variant in exon 5 of FAM20C (c.1007T>G; p. Met336Arg) was identified by targeted Sanger sequencing. Following in silico analysis and mapping of the variant on a three-dimensional (3D) model of FAM20C it is predicted to be deleterious and to affect N-glycosylation, protein folding, and subsequent secretion of FAM20C. In addition, we reviewed all published FAM20C mutations and observed that most pathogenic variants affect functional regions within the protein establishing evidence for an emerging genotype-phenotype correlation. K E Y W O R D S FAM20C, osteosclerosis, Raine syndrome

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Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non‐lethal form of Raine syndrome

Cited by 15 publications

References 17 publications

Natural history of non-lethal Raine syndrome during childhood

Natural history of non-lethal Raine syndrome during childhood

A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age

A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome

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